Experiment Prioritization Index — Neurodegeneration

Experiment Prioritization Index

Overview

Experiment Prioritization Index

Overview

This index ranks experiments by their potential to advance our understanding of neurodegenerative disease mechanisms and accelerate the path to cures. Each experiment is scored on 10 dimensions (0-10 each, max 100).

Related: [Novel Therapy Index](/ideas/novel-therapy-index) | [CBS/PSP Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap) | [Research Gaps](/gaps/rankings)

Scoring Rubric

| Dimension | Weight | Description |
|-----------|--------|-------------|
| Mechanistic Impact | 10% | How much would a definitive result advance fundamental understanding? |
| Cure Proximity | 15% | How directly does this lead to a treatment or cure? |
| Feasibility | 10% | Can this be done with current technology and resources? |
| Cost Efficiency | 10% | Expected insight per dollar invested |
| Timeline | 10% | How quickly can results be obtained? |
| Cross-Disease Value | 10% | Applicable to AD, PD, CBS/PSP, ALS, FTD, HD? |
| Biomarker Enablement | 10% | Would results enable better diagnostics or monitoring? |
| Combinability | 5% | Does the result compound with other experiments? |
| De-risking Value | 10% | Does it reduce risk for expensive clinical programs? |
| Novelty | 10% | Is this a genuinely new approach vs incremental? |

Ranked Experiments

| Rank | Experiment | Category | Score | Disease | Key Question |
|------|-----------|----------|-------|---------|-------------|
| 1 | Head-to-head anti-MTBR-tau antibody comparison (E2814 vs BMS-986446 vs posdinemab) | Clinical | 92 | CBS/PSP/AD | Which anti-tau approach is most effective? |
| 2 | 4R-tau-specific PET tracer validation (PI-2620 vs flortaucipir) | Biomarker | 89 | CBS/PSP | Can we detect 4R-tau with higher sensitivity? |
| 3 | Biomarker-guided tau therapy selection (p-tau217 + NfL + tau PET → treatment algorithm) | Translational | 88 | All tauopathies | Which patients respond to which anti-tau? |
| 4 | iPSC-derived 4R-tau neuron drug screening platform (100+ compounds) | Drug screening | 86 | CBS/PSP | Patient-specific compound efficacy |
| 5 | Combination trial: anti-tau antibody + lithium in PSP | Clinical | 85 | PSP | Does dual tau targeting (aggregation + phosphorylation) synergize? |
| 6 | Tau spreading network mapping via spatial transcriptomics in human PSP brain | Basic mechanism | 84 | PSP | Where does tau start and how does it spread? |
| 7 | Anti-tau + CSF1R inhibitor combination in tauopathy mouse model | Translational | 83 | CBS/PSP | Does reducing neuroinflammation enhance anti-tau efficacy? |
| 8 | IDO1 inhibitor efficacy in 4R-tauopathy model | Drug screening | 82 | CBS/PSP | Does restoring astrocyte energy metabolism reduce tau? |
| 9 | Blood NfL trajectory modeling for PSP progression prediction | Biomarker | 81 | PSP | Can NfL predict rate of decline and treatment response? |
| 10 | Intranasal mitochondrial transplantation in P301S tau mouse model | Translational | 80 | CBS/PSP | Does restoring mitochondrial function slow tau pathology? |
| 11 | Single-nucleus RNA-seq of CBS vs PSP brain tissue (substantia nigra, cortex, brainstem) | Basic mechanism | 79 | CBS/PSP | What determines CBS vs PSP phenotype? |
| 12 | Multi-omics integration (proteomics + metabolomics + transcriptomics) in PSP CSF | Biomarker | 78 | PSP | Novel biomarker discovery and pathway identification |
| 13 | Tau seeding assay from blood (liquid biopsy for 4R-tauopathy) | Biomarker | 77 | CBS/PSP | Can we diagnose tauopathy from a blood draw? |
| 14 | Digital twin modeling of tau propagation in individual patient connectomes | Computational | 76 | CBS/PSP | Predict patient-specific disease trajectory |
| 15 | GLP-1R agonist comparison in tauopathy models (lixisenatide vs semaglutide vs tirzepatide) | Drug screening | 75 | All | Which GLP-1 has best CNS penetration and neuroprotection? |
| 16 | AAV-mediated MAPT knockdown dose-response in non-human primate | Translational | 74 | CBS/PSP | Safe dose range for tau gene therapy |
| 17 | Microglial phenotype characterization in human PSP brain (TREM2, P2RY12, homeostatic vs DAM) | Basic mechanism | 73 | PSP | What microglial states drive PSP neuroinflammation? |
| 18 | O-GlcNAcylation stoichiometry measurement at tau phospho-sites in human PSP brain | Basic mechanism | 72 | PSP | Validate FNP-223 mechanism in human tissue |
| 19 | Pre-symptomatic tau detection: longitudinal blood biomarker study in MAPT mutation carriers | Biomarker | 71 | Genetic FTD/PSP | When does tau pathology become detectable before symptoms? |
| 20 | AlphaFold-based virtual screening of tau aggregation inhibitors (10M+ compound library) | Computational | 70 | All tauopathies | Computationally identify novel tau aggregation blockers |
| 21 | CBS vs PSP phenotype determinants: single-nucleus multi-omics study | Basic mechanism | 77 | CBS/PSP | What molecular factors determine CBS vs PSP from same tau pathology? |
| 22 | Tau spreading network mapping via spatial transcriptomics in PSP brain | Basic mechanism | 75 | PSP | Where does 4R-tau initiate and how does it spread through networks? |
| 23 | Anti-tau antibody vs ASO/gene therapy comparative efficacy in NHP | Translational | 78 | CBS/PSP | Is intracellular or extracellular tau targeting more effective? |
| 24 | Levodopa response predictors: biomarker-guided selection in PSP | Biomarker | 74 | PSP | Why do only 30-40% of PSP patients respond to levodopa? |
| 25 | Tau PET pattern as therapeutic response predictor in 4R-tauopathy | Translational | 76 | CBS/PSP | Which tau PET patterns predict anti-tau therapy response? |
| 26 | Alpha-synuclein aggregation triggers in sporadic PD | Basic mechanism | 77 | PD | What initiates alpha-synuclein aggregation in sporadic PD? |
| 27 | Selective vulnerability of dopaminergic neurons in PD | Basic mechanism | 78 | PD | Why are SNc dopaminergic neurons specifically lost? |
| 28 | Alpha-synuclein prion-like spreading mechanism | Basic mechanism | 76 | PD | Does pathology spreading cause neurodegeneration? |
| 29 | Non-motor symptom progression mechanisms in PD | Basic mechanism | 74 | PD | What drives depression, RBD, constipation progression? |
| 30 | LRRK2/GBA carrier resilience factors | Translational | 79 | PD | Why do some mutation carriers never develop PD? |
| 31 | Levodopa-induced dyskinesias mechanism and prevention in PD | Basic mechanism | 78 | PD | What causes LID and how can it be prevented? |
| 32 | Pre-symptomatic tau detection in MAPT mutation carriers | Biomarker | 75 | PSP/FTD | When does tau become detectable before symptoms? |
| 33 | Tau pathology initiation zone identification (brainstem origin) | Basic mechanism | 77 | CBS/PSP | Where does 4R-tau pathology initiate in the brain? |
| 34 | Blood biomarker vs tau PET for treatment monitoring | Biomarker | 82 | All tauopathies | Can blood biomarkers substitute for tau PET in monitoring? |
| 35 | Sex differences in Alzheimer's disease: mechanisms and therapeutic implications | Basic mechanism | 76 | AD | Why do women have 2x higher AD risk than men? |
| 36 | Microbiome-gut-brain axis in AD: mechanism and intervention | Basic mechanism | 75 | AD | How does gut dysbiosis contribute to AD pathogenesis? |
| 37 | Gut-Brain Axis Pathogenesis in Parkinson's Disease | Basic mechanism | 78 | PD | How does gut dysbiosis trigger alpha-synuclein spreading? |
| 38 | Cognitive reserve mechanisms in AD: molecular basis and enhancement | Translational | 77 | AD | Why do some amyloid-positive people never get dementia? |
| 39 | Viral infections and AD: causal mechanisms and therapeutic implications | Basic mechanism | 72 | AD | Do herpesviruses drive AD pathogenesis? |
| 40 | Sleep disruption and AD: mechanism and intervention | Basic mechanism | 74 | AD | How does sleep-wake cycle disruption accelerate AD? |
| 41 | AD Amyloid-Resilient Phenotype Study | Translational | 76 | AD | Why do some amyloid-positive people never get dementia? |
| 42 | Tau Propagation Causality Test: Does tau spread drive neurodegeneration? | Clinical | 80 | AD/CBS/PSP | Is tau propagation causal to neurodegeneration or a bystander? |
| 43 | Alpha-Syn SAA Kinetics: Biological Staging Backbone for PD | Biomarker | 87 | PD | Do alpha-syn kinetics define distinct progression trajectories? |
| 44 | Prodromal Parkinson's Disease Biomarker Development | Biomarker | 83 | PD | Can we identify PD years before motor symptoms? |
| 45 | Parkinson's Disease Subtype Classification | Translational | 77 | PD | Is PD one disease or several distinct subtypes? |
| 46 | GLP-1 Agonist Responder Prediction: Precision Medicine for PD | Translational | 76 | PD | Which early-PD subgroups benefit from GLP-1 pathway therapies? |
| 47 | Why Does Amyloid Removal Only Slow Decline 27%? | Basic mechanism | 80 | AD | Why do amyloid-clearing antibodies only provide modest benefit? |
| 48 | Selective Vulnerability of Dopaminergic Neurons in PD | Basic mechanism | 78 | PD | Why are SNc neurons selectively lost while VTA survives? |
| 49 | C9orf72 Hexanucleotide Repeat Mechanism in ALS/FTD | Basic mechanism | 75 | ALS/FTD | How does C9orf72 expansion cause ALS vs FTD? |
| 50 | Progranulin Loss and TDP-43 Pathology in FTD | Basic mechanism | 75 | FTD | How does GRN haploinsufficiency lead to TDP-43? |
| 51 | Normal Aging to AD Transition Trigger | Basic mechanism | 78 | AD | What molecular event triggers conversion from aging to AD? |
| 52 | Vascular Contribution to Alzheimer's Disease | Basic mechanism | 75 | AD | How does vascular dysfunction interact with amyloid? |
| 53 | TREM2 Function in Alzheimer's Disease | Translational | 80 | AD | How do TREM2 variants increase AD risk? |
| 54 | TDP-43 PET Ligand Development for FTD and ALS | Biomarker | 81 | FTD/ALS | Can we develop PET tracers for TDP-43 pathology? |
| 55 | Progranulin Replacement Therapy for FTD | Translational | 83 | FTD | Can AAV-GRN restore progranulin and prevent TDP-43? |
| 56 | C9orf72 ALS-FTD Phenotype Mechanism | Basic mechanism | 83 | ALS/FTD | Why does same expansion cause ALS vs FTD? |
| 57 | Viral and Post-Infectious Mechanisms in ALS | Basic mechanism | 71 | ALS | What role do viral infections play in subset of sporadic ALS? |
| 58 | Sleep and Respiratory Network Interaction in ALS | Biomarker | 73 | ALS | How do sleep and respiratory networks interact with progression? |
| 59 | Microbiome-Gut Barrier Signatures in ALS | Basic mechanism | 68 | ALS | Can reproducible microbiome signatures predict ALS progression? |
| 60 | Environmental Exposure Causal Attribution in ALS | Basic mechanism | 64 | ALS | Which environmental exposures are causal vs correlational in ALS? |
| 61 | TDP-43 vs Tau Pathology Determination in GRN vs MAPT Carriers | Basic mechanism | 82 | FTD | What molecular mechanisms switch between TDP-43 and tau pathology in FTD? |
| 62 | GRN Carrier Resilience: Why Some Mutation Carriers Remain Asymptomatic | Translational | 78 | FTD | What protective factors allow some GRN carriers to avoid FTD? |
| 63 | C9orf72 Phenotype Divergence: ALS vs FTD Mechanism Study | Basic mechanism | 81 | FTD/ALS | Why does C9orf72 expansion cause ALS in some and FTD in others? |
| 64 | FTD Microglia Role: Protective vs Destructive Mechanism Study | Basic mechanism | 79 | FTD | What is the role of microglia in FTD progression? |
| 65 | FTLD-Tau vs FTLD-TDP In Vivo Biomarker Differentiation | Biomarker | 84 | FTD | Can we distinguish FTLD-tau from FTLD-TDP in living patients? |
| 66 | Frontal and Temporal Lobe Selective Vulnerability in FTD | Basic mechanism | 75 | FTD | Why are frontal and temporal lobes specifically targeted in FTD? |
| 67 | Presymptomatic GRN Carrier Intervention Timing | Translational | 71 | FTD | When is the optimal time to treat presymptomatic GRN carriers? |
| 68 | TMEM106B Haplotype as Genetic Modifier in FTD | Translational | 73 | FTD | How do TMEM106B haplotypes modify FTD severity? |
| 69 | ALS Progression Rate Heterogeneity: Biomarker Predictors | Biomarker | 79 | ALS | What determines rapid vs slow progression in ALS? |
| 70 | Why Does Amyloid Removal Only Slow Decline 27%? | Basic mechanism | 80 | AD | What limits anti-amyloid antibody clinical efficacy? |
| 71 | Mutant Huntingtin (mHTT) Clearance Mechanisms | Translational | 82 | HD | Which mHTT species are most toxic and how to achieve sustained lowering? |
| 72 | Epigenetic Dysregulation in Huntington's Disease | Basic mechanism | 78 | HD | How does mHTT disrupt epigenetic machinery and can therapies restore patterns? |
| 73 | Microglial Contributions to Huntington's Disease | Basic mechanism | 79 | HD | Do microglia drive neurodegeneration or represent protective responses? |
| 74 | Alpha-Synuclein Staging and Spreading in DLB | Basic mechanism | 81 | DLB | What is the spatial staging pattern of alpha-synuclein in DLB and how does it differ from PD? |
| 75 | Cholinergic System Dysfunction in DLB | Basic mechanism | 79 | DLB | Why are cholinergic deficits more severe in DLB than AD and what drives visual hallucinations? |
| 76 | Cognitive Fluctuation Mechanisms in DLB | Basic mechanism | 83 | DLB | What causes the dramatic cognitive fluctuations in DLB and can they be predicted or prevented? |
| 77 | DLB Treatment Response Biomarkers | Translational | 85 | DLB | Which DLB patients will respond to cholinesterase inhibitors and what determines non-responders? |
| 78 | Metal Ion Homeostasis Dysregulation in AD | Basic mechanism | 65 | AD | How do copper, zinc, and iron dysregulation contribute to amyloid aggregation? |
| 79 | ApoE4 Function in Alzheimer's Disease | Translational | 75 | AD | How does ApoE4 confer AD risk at the cellular level? |
| 80 | Traumatic Brain Injury and AD Relationship | Basic mechanism | 58 | AD | Is TBI a causal risk factor for later AD development? |
| 81 | Lifestyle Intervention Mechanisms in AD | Basic mechanism | 72 | AD | What molecular mechanisms mediate exercise, diet, and cognitive reserve benefits? |
| 82 | MSA-P vs MSA-C Subtype Biomarker Discovery | Biomarker | 76 | MSA | How can biological subtypes be defined using multimodal biomarkers? |
| 83 | Iron Dyshomeostasis in MSA Pathogenesis | Basic mechanism | 77 | MSA | What causal role does iron dyshomeostasis play in MSA propagation? |
| 84 | Sleep-Disordered Breathing in MSA Progression | Biomarker | 73 | MSA | What drives severe sleep-disordered breathing and stridor in MSA? |
| 85 | MSA vs PD Alpha-Synuclein Strain Differences | Basic mechanism | 80 | MSA/PD | Do MSA and PD have distinct alpha-synuclein strains? |
| 86 | MSA GCI Formation Mechanism | Basic mechanism | 77 | MSA | What drives GCI formation specifically in MSA oligodendrocytes? |
| 87 | MSA Autonomic Failure Mechanism | Translational | 75 | MSA | Why does MSA have more severe autonomic failure than PD? |
| 88 | Prion Strain Diversity and Selective Vulnerability in CJD | Basic mechanism | 74 | Prion | How do prion strain variants determine clinical phenotype and neuronal vulnerability? |
| 89 | Pre-Symptomatic Detection and Intervention Timing in Genetic Prion Disease | Biomarker | 72 | Prion | Can we develop biomarkers to detect pre-symptomatic genetic prion disease and guide intervention timing? |
| 90 | Prion Propagation Mechanism: Cell-to-Cell Transmission and Neurotoxicity | Basic mechanism | 76 | Prion | What are the mechanisms of prion spread between neurons and glia, and which species cause neurotoxicity? |
| 91 | Anti-Prion Therapeutic Development: HTS and Validation | Translational | 78 | Prion | Can we identify compounds that prevent prion conversion and clear existing aggregates? |
| 92 | DLB Cognitive Fluctuation Mechanism | Basic mechanism | 78 | DLB | What molecular and network mechanisms cause dramatic cognitive fluctuations? |
| 93 | NPH Glymphatic System Interaction | Basic mechanism | 81 | NPH | How does glymphatic dysfunction interact with CSF dynamics in NPH? |
| 94 | EBV as Causal Trigger vs Necessary Co-factor in MS Neurodegeneration | Basic mechanism | 83 | MS | Is EBV a causal driver or necessary but insufficient co-factor in MS? |
| 95 | CSF Dynamic Biomarkers for Differential Diagnosis of NPH vs AD with Concomitant NPH | Biomarker | 82 | NPH/AD | Can CSF biomarkers distinguish iNPH from AD with comorbid NPH to guide shunting decisions? |
| 96 | Migraine Cortical Hyperexcitability and Alzheimer's Disease Risk | Basic mechanism | 80 | Migraine/AD | Does migraine hyperexcitability drive AD risk via tau phosphorylation, and can CGRP therapies help? |
| 97 | Biomechanical Impact Profiles and CTE Phenotype Heterogeneity | Basic mechanism | 85 | TBI/CTE | Which impact profiles drive which CTE pathological subtypes and clinical phenotypes? |
| 98 | Selective Neuronal Vulnerability to Aging (Score: 67, rank 98) | Basic mechanism | 67 | Cross-neurodegeneration | Why specific neuronal subtypes (SNc, entorhinal, basal forebrain) fail with age while neighbors survive — and how to protect them |
| 99 | Blood-Brain Barrier Aging and Neurodegeneration (Score: 63, rank 99) | Basic mechanism | 63 | Cross-neurodegeneration | Does BBB breakdown actively drive neurodegeneration, and can restoring BBB integrity slow disease progression? |
| 100 | Epigenetic Clocks in Neurodegeneration — Causal vs. Marker (Score: 66, rank 100) | Basic mechanism | 66 | Cross-neurodegeneration | Are epigenetic aging clocks causal drivers of neurodegeneration or merely correlative markers of biological age? |
| 101 | Microglial Aging and Immune Memory in Neurodegeneration (Score: 65, rank 101) | Basic mechanism | 65 | Cross-neurodegeneration | Does trained immunity accumulate in microglia over the lifespan and drive chronic neuroinflammation that promotes neurodegeneration? |
| 102 | Vascular Contributions to Mixed AD/VaD Pathology | Basic mechanism | 77 | AD/VaD | How does vascular dysfunction interact with amyloid and tau pathology in mixed dementia, and can addressing vascular health enhance therapeutic efficacy? |
| 103 | Down Syndrome Alzheimer's Disease: Mechanisms and Therapeutic Timing | Translational | 82 | DS-AD | What are optimal intervention timing and mechanisms in DS-AD, the largest genetic form of AD, and does early amyloid removal prevent later tau and cognitive decline? |
| 104 | FXTAS Phenotypic Penetrance: Why Only 40% of FMR1 Premutation Carriers Develop FXTAS | Basic mechanism | 76 | FXTAS | What genetic, epigenetic, and environmental modifiers determine which FMR1 premutation carriers develop FXTAS? |
| 105 | Wilson Disease Neurodegeneration: Mechanism and Therapeutic Response | Basic mechanism | 71 | Wilson Disease | Why do only 40-50% of WD patients develop neurological symptoms, and what predicts treatment response? |
| 10 | Anti-Tau Therapy Failure Mechanism in PSP (Score: 78, rank 107) | Basic mechanism | 78 | PSP | Why have anti-tau antibody trials failed in PSP and what will make next trials succeed? |
| 106 | Spinocerebellar Ataxia Disease-Modifying Therapy Development | Translational | 78 | SCA | Can we develop effective disease-modifying therapies for SCAs by targeting polyQ toxicity and enhancing autophagic clearance? |
| 107 | RBD and Autonomic Dysfunction in DLB Progression | Basic mechanism | 74 | DLB | How do REM sleep behavior disorder and autonomic dysfunction relate to disease progression in DLB? |
| 108 | Tau Co-Pathology in DLB Clinical Heterogeneity | Basic mechanism | 71 | DLB | How does tau co-pathology influence clinical presentation, progression, and treatment response in DLB? |
| 109 | Genetic Risk Modifiers in DLB Phenotype | Translational | 72 | DLB | How do GBA, SNCA, and APOE genetic variants modify DLB clinical phenotype and treatment response? |
| 110 | Mixed Pathology Effects on Parkinson's Disease Progression and Treatment Response | Basic mechanism | 78 | PD | How do AD co-pathology, vascular burden, and tau pathology alter PD progression trajectories and treatment response? |
| 111 | Sleep and Circadian Dysfunction as Driver of Neurodegeneration | Basic mechanism | 83 | Cross-neurodegeneration | Is sleep disruption causal in neurodegeneration or merely a biomarker, and can sleep/circadian restoration slow progression? |

Categories

Basic Mechanism (understanding how disease works)

Translational (bridging lab to clinic)

Biomarker (better diagnosis and monitoring)

Drug Screening (finding new treatments)

Clinical (human trials)

Computational (in silico modeling)

How to Use This Index

See Also

• [Novel Therapy Index](/ideas/novel-therapy-index)
• [Research Gaps Rankings](/gaps/rankings)
• [CBS/PSP Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap)
• [Experiment Index](/experiments/experiment-index)