Experiment Prioritization Index — Neurodegeneration

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?

¶ Experiment Prioritization Index

¶ Overview

¶ Scoring Rubric

¶ Ranked Experiments

¶ 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