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)
| 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? |
| 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? |