Novel Therapy Index

Novel Therapy Index

Related Pages

[Alzheimer's Disease](/diseases/alzheimers-disease) | [Parkinson's Disease](/diseases/parkinsons-disease) | [Amyotrophic Lateral Sclerosis](/diseases/als-ftd-spectrum) | [Frontotemporal Dementia](/diseases/frontotemporal-dementia) | [Progressive Supranuclear Palsy](/diseases/psp) | [Multiple System Atrophy](/diseases/multiple-system-atrophy) | [Tau Protein](/proteins/tau) | [Alpha-Synuclein](/proteins/alpha-synuclein) | [TDP-43](/proteins/tdp-43-protein) | [Neuroinflammation](/mechanisms/neuroinflammation) | [Oxidative Stress](/mechanisms/oxidative-stress-pathway) | [Autophagy Dysfunction](/mechanisms/autophagy-lysosomal-pathway) | [Therapeutics](/therapeutics)

Overview

This page is NeuroWiki's invention-lab hub for new therapeutic concepts built from existing mechanistic evidence in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Progressive Supranuclear Palsy (PSP), and aging-linked proteinopathy. The goal is to prioritize ideas that can be operationalized into near-term translational programs, rather than just cataloging speculative hypotheses.

The ranking rubric uses 10 dimensions (0-10 each, maximum 100): Novelty, Mechanistic Rationale, Root-Cause Coverage, Delivery Feasibility, Safety Plausibility, Combinability, Biomarker Availability, De-risking Path, Multi-disease Potential, and Patient Impact.

Ranked Idea Table

Novel Therapy Index

Related Pages

[Alzheimer's Disease](/diseases/alzheimers-disease) | [Parkinson's Disease](/diseases/parkinsons-disease) | [Amyotrophic Lateral Sclerosis](/diseases/als-ftd-spectrum) | [Frontotemporal Dementia](/diseases/frontotemporal-dementia) | [Progressive Supranuclear Palsy](/diseases/psp) | [Multiple System Atrophy](/diseases/multiple-system-atrophy) | [Tau Protein](/proteins/tau) | [Alpha-Synuclein](/proteins/alpha-synuclein) | [TDP-43](/proteins/tdp-43-protein) | [Neuroinflammation](/mechanisms/neuroinflammation) | [Oxidative Stress](/mechanisms/oxidative-stress-pathway) | [Autophagy Dysfunction](/mechanisms/autophagy-lysosomal-pathway) | [Therapeutics](/therapeutics)

Overview

This page is NeuroWiki's invention-lab hub for new therapeutic concepts built from existing mechanistic evidence in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Progressive Supranuclear Palsy (PSP), and aging-linked proteinopathy. The goal is to prioritize ideas that can be operationalized into near-term translational programs, rather than just cataloging speculative hypotheses.

The ranking rubric uses 10 dimensions (0-10 each, maximum 100): Novelty, Mechanistic Rationale, Root-Cause Coverage, Delivery Feasibility, Safety Plausibility, Combinability, Biomarker Availability, De-risking Path, Multi-disease Potential, and Patient Impact.

Ranked Idea Table

Only fully developed ideas with dedicated pages are ranked. Ideas without pages are listed in the Placeholder section below.

| Rank | Idea | Category | AD | PD | ALS | FTD | PSP | MSA | Aging | Total Score |
| 74 | [Focal Adhesion Kinase (FAK) Inhibition Therapy](ideas/payload-fak-inhibition-neurodegeneration) | Novel target (FAK signaling) | 8 | 8 | 7 | 6 | 6 | 0 | 7 | 74 |
| 75 | [HIF-1α Stabilization Therapy for Neurodegeneration](ideas/payload-hif1-alpha-stabilization-therapy) | Novel target (hypoxia response) | 8 | 8 | 8 | 7 | 6 | 0 | 9 | 75 |
| 76 | [Ketone Body Therapeutic Strategy for Neurodegeneration](ideas/payload-ketone-body-therapeutic-strategy) | Novel target (metabolic therapy) | 9 | 7 | 6 | 6 | 6 | 0 | 8 | 81 |
|---|---|---|---:|---:|---:|---:|---:|---:|
| 1 | [TDP-43 Splicing Modulation Therapy](ideas/payload-tdp43-splicing-modulation-therapy) | Novel target (splicing) | 9 | 9 | 9 | 8 | 5 | 0 | 6 | 80 |
| 2 | [SIRT1 Activation + NAD+ Precursor Combination Therapy](ideas/combo-sirt1-nad-epigenetic-metabolic) | Combination logic | 8 | 8 | 7 | 7 | 7 | 0 | 9 | 85 |
| 112 | [Perivascular Space Drainage Enhancement Therapy](ideas/payload-perivascular-drainage-enhancement-therapy) | Novel target (glymphatic-lymphatic) | 9 | 8 | 9 | 8 | 5 | 0 | 8 | 85 |
| 86 | [Calcium Homeostasis Modulation Therapy for Neurodegeneration](ideas/payload-calcium-homeostasis-modulation-therapy) | Novel target (calcium homeostasis) | 9 | 9 | 7 | 6 | 7 | 0 | 9 | 79 |
| 3 | [C9orf72 RNA-Targeting for DPR Reduction](ideas/c9orf72-rna-targeting-dpr-reduction) | Payload design (ASO/RNAi) | 3 | 3 | 10 | 9 | 3 | 0 | 5 | 84 |
| 4 | [NfL-Guided Neuroprotection Threshold](ideas/biomarker-nfl-neuroprotection-threshold) | Biomarker-driven | 8 | 8 | 6 | 7 | 8 | 0 | 8 | 84 |
| 5 | [Intranasal Insulin + GLP-1 Combination Therapy](ideas/payload-insulin-glp1-combo-therapy) | Combination logic + repurposing | 8 | 8 | 5 | 6 | 6 | 0 | 8 | 82 |
| 6 | [Microglia-state editing via TREM2-LXR pulse program](ideas/payload-microglia-state-editing-trem2-lxr) | Novel target + biomarker-driven | 9 | 7 | 5 | 8 | 8 | 0 | 6 | 82 |
| 7 | [GBA1 Gaucher Disease Modulator for Parkinson's Disease](ideas/payload-gba1-gaucher-modulator) | Novel target | 8 | 9 | 2 | 2 | 5 | 0 | 6 | 80 |
| 8 | [Astrocyte-to-Neuron Direct Reprogramming Therapy](ideas/astrocyte-neuron-reprogramming) | Regeneration | 8 | 8 | 8 | 7 | 6 | 0 | 8 | 80 |
| 9 | [Mitophagy gate therapy: PINK1/Parkin plus lysosomal TFEB priming](ideas/payload-mitophagy-gate-therapy) | Combination logic | 7 | 9 | 8 | 6 | 8 | 0 | 8 | 80 |
| 10 | [SARM1 NADase Inhibition for Axonal Preservation](ideas/payload-sarm1-nadase-inhibitor) | Novel target | 3 | 8 | 9 | 2 | 6 | 0 | 7 | 80 |
| 11 | [VPS35 Retromer Stabilizer for Lysosomal Rescue](ideas/vps35-retromer-stabilizer) | Novel target | 8 | 9 | 7 | 7 | 6 | 0 | 8 | 80 |
| 12 | [p-Tau217 Adaptive Dosing Protocol](ideas/biomarker-ptau217-adaptive-dosing) | Biomarker-driven | 9 | 5 | 4 | 8 | 8 | 0 | 5 | 80 |
| 13 | [NUS1 CoQ10 Pathway Modulation for Parkinson's Disease](ideas/payload-nus1-cog10-pathway-modulation) | Novel target | 6 | 9 | 4 | 2 | 5 | 0 | 7 | 79 |
| 14 | [CB1 Receptor Endocannabinoid Modulation Therapy](ideas/cb1-endocannabinoid-modulation-therapy) | Novel target + biomarker-driven | 8 | 9 | 8 | 6 | 6 | 0 | 7 | 79 |
| 15 | [Tau-PROTAC Heterobifunctional Degrader](ideas/payload-tau-protac-degrader) | Payload design | 9 | 5 | 4 | 9 | 8 | 0 | 5 | 79 |
| 16 | [ESCRT-III Neuroprotection Therapy for Neurodegeneration](ideas/payload-escrthost-III-neuroprotection-therapy) | Novel target (ESCRT-III/membrane scission) | 9 | 9 | 8 | 6 | 7 | 0 | 9 | 79 |
| 16 | [Sigma-1 Receptor Agonist Therapy](ideas/sigma1-receptor-agonist-therapy) | Novel target + delivery | 9 | 8 | 8 | 6 | 6 | 0 | 8 | 79 |
| 17 | [Complement Pathway Inhibition Therapy for Neurodegeneration](ideas/payload-complement-pathway-inhibition-therapy) | Novel target (complement cascade) | 8 | 9 | 7 | 6 | 7 | 0 | 8 | 79 |
| 18 | [Ferroptosis Inhibition Therapy](ideas/payload-ferroptosis-inhibitor) | Novel target | 8 | 8 | 8 | 6 | 7 | 0 | 7 | 78 |
| 18 | [CRMP2 Phosphorylation State Modulation Therapy for Neurodegeneration](ideas/payload-crmp2-phosphorylation-modulation-therapy) | Novel target (cytoskeletal/transport) | 8 | 8 | 9 | 6 | 7 | 5 | 8 | 77 |
| 19 | [HDAC6 Modulation Therapy for Neurodegeneration](ideas/payload-hdac6-modulation-therapy) | Novel target | 8 | 9 | 7 | 6 | 6 | 0 | 7 | 78 |
| 19 | [Neurogranin-Synapse Rescue Cascade](ideas/biomarker-neurogranin-synapse-rescue) | Biomarker-driven | 8 | 7 | 6 | 6 | 5 | 0 | 6 | 78 |
| 20 | [Proteostasis Triad Pulses: ISR + Autophagy + Chaperone Induction](ideas/payload-proteostasis-triad-pulses) | Combination logic | 8 | 8 | 8 | 8 | 8 | 0 | 8 | 78 |
| 21 | [Mitochondrial Dynamics Modulation Therapy (DRP1/Miro1)](ideas/payload-mitochondrial-dynamics-modulation-therapy) | Novel target | 8 | 9 | 7 | 6 | 7 | 0 | 8 | 78 |
| 22 | [Tau-seed interception using conformer-selective extracellular traps](ideas/idea-tau-seed-interception) | Payload design | 9 | 5 | 4 | 9 | 9 | 0 | 5 | 78 |
| 23 | [ULK1/2 Kinase Modulation for Mitophagy Induction](ideas/ulnk1-2-kinase-modulation-mitophagy) | Novel target | 8 | 9 | 7 | 6 | 7 | 0 | 8 | 78 |
| 24 | [CSPG-PNN Modulation for Synaptic Plasticity Enhancement](ideas/payload-cspg-pnn-modulation-synaptic-plasticity) | Regeneration & reversal | 8 | 8 | 7 | 6 | 5 | 0 | 7 | 78 |
| 25 | [YKL-40 Anti-Inflammatory Cycling](ideas/biomarker-ykl40-antiinflammatory-cycling) | Biomarker-driven | 7 | 7 | 6 | 5 | 7 | 0 | 7 | 78 |
| 26 | [cGAS-STING Pathway Inhibition](ideas/cgas-sting-pathway-inhibitor) | Novel target | 8 | 8 | 8 | 8 | 6 | 0 | 7 | 77 |
| 27 | [CD38 Inhibition + NAD+ Precursor Synergy](ideas/cd38-inhibition-nad-synergy) | Combination logic | 8 | 8 | 5 | 4 | 7 | 0 | 7 | 77 |
| 28 | [AAV-Delivered RNA Targeting Therapy](ideas/payload-aav-rna-targeting-neurodegeneration) | Payload design (AAV+RNA) | 8 | 9 | 8 | 6 | 7 | 0 | 7 | 77 |
| 29 | [REST Preservation Therapy for Neurodegeneration](ideas/payload-rest-preservation-therapy) | Novel target | 8 | 9 | 8 | 8 | 6 | 0 | 8 | 77 |
| 30 | [Adenine Base Editing of APOE4 to APOE3](ideas/payload-base-editing-apoe4) | Payload design (base editing) | 9 | 3 | 3 | 5 | 4 | 0 | 7 | 76 |
| 31 | [VCP Proteostasis Modulation for ALS/FTD](ideas/payload-vcp-proteostasis-modulation) | Novel target | 6 | 5 | 9 | 9 | 6 | 0 | 6 | 76 |
| 32 | [Astrocyte glutamate-buffer rescue with EAAT2 transcription reboot](ideas/payload-eaat2-glutamate-buffer-rescue) | Novel target | 7 | 8 | 8 | 6 | 6 | 0 | 6 | 76 |
| 33 | [CRISPRi epigenetic silencing of SNCA](ideas/payload-crispri-snca-silencing) | Payload design (epigenetic editor) | 3 | 9 | 4 | 7 | 2 | 0 | 5 | 76 |
| 34 | [LRRK2 Inhibitor Therapy](ideas/lrrk2-inhibitor-therapy) | Novel target | 2 | 9 | 2 | 2 | 3 | 0 | 5 | 76 |
| 35 | [Lipophagy Activation Therapy for Neurodegeneration](ideas/lipophagy-activation-therapy) | Novel target | 8 | 8 | 7 | 6 | 6 | 0 | 7 | 76 |
| 36 | [Molecular glue for TDP-43 aggregate clearance](ideas/payload-molecular-glue-tdp43) | Payload design (molecular glue) | 5 | 3 | 9 | 9 | 4 | 0 | 5 | 76 |
| 37 | [sTREM2-Modulated Microglial Therapy](ideas/biomarker-strem2-microglial-modulation) | Biomarker-driven | 8 | 6 | 5 | 7 | 8 | 0 | 5 | 76 |
| 103 | [Nucleocytoplasmic Transport Modulation Therapy for ALS/FTD](ideas/payload-nucleocytoplasmic-transport-modulation-therapy) | Novel target (NCT) | 6 | 5 | 10 | 10 | 4 | 0 | 7 | 78 |
| 38 | [ATTEC Autophagy-Targeting Chimera for Neurodegeneration](ideas/payload-attect-alpha-synuclein) | Payload design (ATTEC) | 9 | 9 | 8 | 8 | 8 | 0 | 6 | 75 |
| 39 | [Prodromal Resilience Package for Genetically High-Risk Cohorts](ideas/payload-prodromal-resilience-package) | Prevention/resilience | 9 | 8 | 7 | 7 | 6 | 0 | 9 | 75 |
| 40 | [Astrocytic Mitochondrial Transfer + Metabolic Copacking](ideas/payload-astrocyte-mito-transfer-metabolic-copacking) | Combination logic | 8 | 8 | 7 | 5 | 6 | 0 | 8 | 75 |
| 41 | [GPNMB Modulation for Lipid-Laden Microglia Rescue](ideas/gpnmb-modulator) | Novel target | 8 | 8 | 6 | 7 | 7 | 0 | 7 | 75 |
| 42 | [Synthetic Gene Circuit for Feedback-Controlled GDNF](ideas/payload-gene-circuit-gdnf) | Payload design (gene circuit) | 3 | 9 | 4 | 6 | 5 | 0 | 6 | 75 |
| 43 | [USP13 Inhibitor for Mitophagy and Synaptic Proteostasis](ideas/usp13-inhibitor) | Novel target | 7 | 8 | 7 | 6 | 7 | 0 | 7 | 75 |
| 44 | [Gut-Microbiome-Targeted Therapeutic](ideas/gut-microbiome-targeted-therapeutic) | Novel target + biomarker-driven | 8 | 9 | 6 | 6 | 6 | 0 | 7 | 74 |
| 45 | [NLRP3-coupled senomorphic cycling therapy](ideas/nlrp3-senomorphic-cycling-therapy) | Repurposing + combination | 8 | 7 | 6 | 7 | 7 | 0 | 8 | 74 |
| 46 | [Senolytic Therapy for Neurodegeneration](ideas/senolytic-therapy-neurodegeneration) | Novel target | 8 | 8 | 7 | 7 | 7 | 0 | 9 | 74 |
| 47 | [UFM1ylation Modulation for Proteostasis Restoration](ideas/payload-ufm1ylation-proteostasis-restoration) | Novel target | 8 | 8 | 8 | 6 | 7 | 0 | 9 | 74 |
| 48 | [mRNA-encoded Intrabody for Alpha-Synuclein](ideas/payload-mrna-intrabody-synuclein) | Payload design (mRNA) | 3 | 9 | 4 | 7 | 2 | 0 | 4 | 74 |
| 49 | [UFM1ylation Modulation for Neurodegeneration](ideas/payload-ufm1ylation-modulation) | Novel target | 8 | 8 | 7 | 8 | 7 | 0 | 7 | 74 |
| 50 | [HSP90 Co-chaperone CDC37 Modulation](ideas/hsp90-cdc37-modulation) | Novel target | 8 | 8 | 7 | 7 | 7 | 0 | 7 | 73 |
| 51 | [Autophagy-Proteostasis Dual Activation Therapy](ideas/payload-autophagy-proteostasis-dual-activation) | Combination logic | 8 | 8 | 8 | 8 | 8 | 0 | 7 | 73 |
| 52 | [FXR Modulation Therapy for Neurodegeneration](ideas/fxr-modulation-therapy) | Novel target | 8 | 8 | 7 | 6 | 5 | 0 | 7 | 73 |
| 53 | [RIPK1-TAK1 Interaction Inhibitor](ideas/payload-ripk1-tak1-inhibitor) | Novel target (PPI) | 7 | 8 | 7 | 6 | 6 | 0 | 7 | 72 |
| 54 | [BBB-Transcytosis Shuttle for CNS PROTAC Delivery](ideas/bbb-transcytosis-shuttle-protac-delivery) | Delivery innovation | 8 | 7 | 5 | 6 | 8 | 0 | 7 | 72 |
| 55 | [Engineered iPSC-Microglia Cell Therapy](ideas/payload-ipsc-microglia-therapy) | Payload design (cell therapy) | 8 | 6 | 5 | 6 | 7 | 0 | 8 | 72 |
| 56 | [Synapse-resilience circuit: BDNF plus sleep-glymphatic entrainment](ideas/synapse-resilience-bdnf-glymphatic) | Regeneration + prevention | 8 | 7 | 4 | 5 | 7 | 0 | 7 | 71 |
| 57 | [LRRK2 Kinase Modulation for Pre-symptomatic PD Prevention](ideas/payload-lrrk2-kinase-modulation-prevention) | Prevention/resilience | 8 | 9 | 7 | 7 | 2 | 0 | 7 | 69 |
| 58 | [GBA1 Enzyme Enhancement for Pre-symptomatic PD Prevention](ideas/payload-gba-enzyme-enhancement-prevention) | Prevention/resilience | 7 | 9 | 8 | 8 | 2 | 0 | 8 | 72 |
| 59 | [Circadian Entrainment for Neurodegeneration Prevention](ideas/payload-circadian-entrainment-neuroprevention) | Prevention/resilience | 6 | 9 | 7 | 9 | 7 | 0 | 10 | 78 |
| 60 | [Microbiome-Guided Prevention Bundle](ideas/payload-microbiome-guided-prevention-bundle) | Prevention/resilience | 7 | 9 | 7 | 9 | 6 | 0 | 9 | 80 |
| 61 | [Senolytic Prevention Protocol](ideas/payload-senolytic-prevention-protocol) | Prevention/resilience | 8 | 9 | 8 | 7 | 7 | 0 | 9 | 74 |
| 62 | [Synaptic Resilience Enhancement](ideas/payload-synaptic-resilience-enhancement) | Prevention/resilience | 7 | 9 | 8 | 9 | 6 | 0 | 9 | 82 |
| 63 | [circRNA Dysfunction Restoration](ideas/circrna-dysfunction-restoration) | Novel target | 8 | 8 | 6 | 6 | 6 | 0 | 7 | 71 |
| 64 | [Mitochondrial NAD Redox Swing Protocol](ideas/payload-mitochondrial-nad-redox-swing) | Biomarker-driven | 8 | 8 | 6 | 5 | 7 | 0 | 7 | 70 |
| 65 | [TMEM175 Lysosomal K+ Channel Modulation](ideas/payload-tmem175-lysosomal-modulation) | Novel target | 8 | 9 | 2 | 2 | 4 | 0 | 5 | 74 |
| 66 | [NRF2 Activator Therapy](ideas/payload-nrf2-activator-therapy) | Novel target | 8 | 8 | 8 | 7 | 8 | 0 | 9 | 82 |
| 67 | [Klotho Anti-Aging Therapy: Multi-Modal Neuroprotection](ideas/payload-klotho-anti-aging-therapy) | Novel target | 8 | 9 | 9 | 7 | 7 | 0 | 8 | 76 |
| 68 | [GLP-1 Receptor Agonist Therapy](ideas/payload-glp1-receptor-agonist-therapy) | Repurposing + novel target | 8 | 8 | 7 | 7 | 7 | 0 | 8 | 78 |
| 69 | [GSK-3 Inhibitor Therapy](ideas/payload-gsk3-inhibitor-therapy) | Novel target | 8 | 9 | 8 | 6 | 8 | 0 | 7 | 78 |
| 70 | [Sigma-1 Receptor Agonist Therapy](ideas/payload-sigma1-receptor-agonist-therapy) | Novel target | 8 | 7 | 8 | 7 | 6 | 0 | 8 | 76 |
| 71 | [Adenosine A2A Receptor Antagonist Therapy](ideas/payload-adenosine-a2a-receptor-antagonist-therapy) | Repurposing | 8 | 8 | 5 | 9 | 6 | 0 | 8 | 75 |
| 72 | [TAM Receptor Modulation Therapy](ideas/payload-tam-receptor-modulation-therapy) | Novel target | 8 | 8 | 7 | 7 | 7 | 0 | 7 | 73 |
| 73 | [Simufilam (Aβ Oligomer Antagonist) Therapy](ideas/payload-simufilam-therapy) | Novel target | 9 | 8 | 3 | 3 | 2 | 0 | 6 | 73 |
| 74 | [HSP70 Inducer Therapies](ideas/payload-hsp70-inducer-therapy) | Novel target | 8 | 9 | 7 | 7 | 7 | 0 | 7 | 72 |
| 75 | [PARP Inhibitor Therapy](ideas/payload-parp-inhibitor-therapy) | Repurposing | 7 | 8 | 7 | 7 | 6 | 0 | 7 | 72 |
| 76 | [CX3CR1 Modulation Therapy](ideas/payload-cx3cr1-modulation-therapy) | Novel target | 8 | 8 | 7 | 7 | 7 | 0 | 8 | 71 |
| 77 | [SOD1 Targeted RNA Silencing Therapy for ALS](ideas/payload-sod1-targeted-rna-silencing-therapy) | Payload design (ASO/RNAi) | 2 | 2 | 10 | 4 | 2 | 0 | 5 | 72 |
| 78 | [TGF-β Modulation Therapy for Neurodegeneration](ideas/payload-tgf-beta-modulation-therapy) | Novel target | 8 | 8 | 7 | 7 | 7 | 0 | 7 | 72 |
| 78 | [Tau PET-Guided Tau Immunotherapy](ideas/biomarker-tau-pet-guided-immunotherapy) | Biomarker-driven | 8 | 7 | 6 | 6 | 9 | 0 | 7 | 78 |
| 79 | [Epigenetic Clock Reversal Therapy for Neurodegeneration Prevention](ideas/payload-epigenetic-clock-reversal-therapy) | Prevention/resilience | 9 | 8 | 7 | 7 | 6 | 0 | 10 | 79 |
| 80 | [Alpha-Synuclein RT-QuIC-Guided Therapy](ideas/biomarker-alpha-synuclein-rtquic-therapy) | Biomarker-driven | 8 | 7 | 5 | 6 | 1 | 0 | 6 | 77 |
| 81 | [GFAP-Guided Astrocyte Modulation Therapy](ideas/biomarker-gfap-astrocyte-modulation) | Biomarker-driven | 8 | 7 | 5 | 6 | 7 | 0 | 7 | 77 |
| 82 | [DNA Damage Repair Therapy — 8-OHdG Guided](ideas/biomarker-dna-damage-repair-therapy) | Biomarker-driven | 7 | 8 | 6 | 5 | 6 | 0 | 6 | 76 |
| 83 | [CSF Aβ42/Aβ40 Ratio-Guided Anti-Amyloid Therapy](ideas/biomarker-abeta-42-40-ratio-therapy) | Biomarker-driven | 9 | 7 | 5 | 6 | 2 | 0 | 7 | 80 |
| 84 | [Biomarker-Guided Therapy Overview](ideas/biomarker-guided-therapy-overview) | Framework | 9 | 6 | 4 | 5 | 7 | 0 | 8 | 78 |

| 85 | [AMPK Agonist Therapy for Neurodegeneration](ideas/payload-ampk-agonist-neurodegeneration) | Novel target | 9 | 8 | 7 | 6 | 7 | 0 | 8 | 79 |
| 86 | [Wnt Pathway Modulation for Synaptic Resilience](ideas/payload-wnt-pathway-modulation-synaptic-resilience) | Novel target | 8 | 8 | 7 | 7 | 6 | 0 | 7 | 77 |
| 86 | [GABA Receptor Modulation Therapy](ideas/payload-gaba-receptor-modulation-therapy) | Novel target | 8 | 8 | 6 | 7 | 7 | 6 | 8 | 78 |

| 113 | [AAV Capsid Engineering for CNS-Targeted Neurodegeneration Therapy](ideas/payload-aav-capsid-engineering-cns-therapy) | Delivery innovation (capsid) | 8 | 9 | 9 | 8 | 7 | 6 | 8 | 82 |
| 87 | [CX3CR1 Modulation Therapy for Neurodegeneration](ideas/payload-cx3cr1-modulation-therapy) | Novel target (neuroinflammation) | 9 | 9 | 8 | 7 | 7 | 0 | 9 | 75 |
| 88 | [Perivascular Macrophage Neuroprotection Therapy](ideas/perivascular-macrophage-neuroprotection-therapy) | Delivery Innovation | 9 | 7 | 0 | 6 | 0 | 0 | 8 | 74 |
| 89 | [sGC Stimulator Therapy for Neurodegeneration](ideas/payload-sgc-stimulator-therapy) | Novel target (cGMP signaling) | 8 | 8 | 7 | 7 | 6 | 0 | 7 | 74 |
| 89 | [ROCK Inhibitor Therapy for Neurodegeneration](ideas/payload-rock-inhibitor-therapy) | Novel target (cytoskeleton) | 8 | 8 | 7 | 7 | 7 | 0 | 7 | 72 |
| 90 | [4R-Tau Targeting Therapy for PSP](ideas/payload-4r-tau-targeting-therapy) | Novel target (4R-tauopathy) | 3 | 2 | 2 | 5 | 10 | 3 | 4 | 79 |
| 91 | [Brainstem Circuit Modulation Therapy for PSP](ideas/payload-brainstem-circuit-modulation-therapy) | Novel target (brainstem circuits) | 4 | 8 | 4 | 5 | 10 | 8 | 5 | 75 |
| 92 | [Alpha-Synuclein Aggregation Inhibition Therapy for MSA](ideas/payload-alpha-synuclein-aggregation-inhibition-therapy) | Novel target (α-syn aggregation) | 2 | 8 | 2 | 3 | 3 | 10 | 4 | 76 |
| 93 | [MSA Combination Therapy](ideas/payload-msa-combination-therapy) | Combination logic | 3 | 5 | 2 | 3 | 6 | 10 | 4 | 77 |
| 94 | [Cerebellar Circuit Protection Therapy for MSA](ideas/payload-cerebellar-circuit-protection-therapy) | Novel target (cerebellar circuits) | 3 | 4 | 3 | 3 | 6 | 10 | 4 | 74 |
| 95 | [Autonomic Dysfunction Targeting Therapy for MSA](ideas/payload-autonomic-dysfunction-targeting-therapy) | Novel target (autonomic) | 3 | 7 | 4 | 3 | 5 | 10 | 6 | 72 |
| 96 | [PSP Combination Therapy](ideas/payload-psp-combination-therapy) | Combination logic | 3 | 2 | 2 | 5 | 10 | 3 | 4 | 77 |
| 97 | [Progranulin Restoration Therapy for FTD](ideas/payload-progranulin-restoration-therapy-ftd) | Novel target (gene therapy) | 3 | 3 | 6 | 10 | 3 | 2 | 5 | 80 |
| 98 | [Tau Propagation Blocker Therapy for PSP](ideas/payload-tau-propagation-blocker-therapy) | Payload design (propagation) | 7 | 8 | 7 | 6 | 8 | 7 | 7 | 75 |
| 99 | [Hippo Pathway Modulation Therapy for CBS](ideas/payload-hippo-pathway-modulation-cbs) | Novel target (Hippo pathway) | 10 | 3 | 2 | 6 | 9 | 8 | 5 | 76 |
| 100 | [Huntington's Disease Gene Silencing Therapy](ideas/payload-huntingtons-gene-silencing-therapy) | Payload design (ASO/RNAi) | 3 | 3 | 3 | 3 | 3 | 0 | 3 | 78 |
| 101 | [DLB Cholinergic Circuit Modulation Therapy](ideas/payload-dlb-cholinergic-circuit-modulation-therapy) | Novel target (cholinergic) | 3 | 5 | 3 | 3 | 3 | 0 | 5 | 76 |
| 102 | [Oligodendrocyte Protection Therapy for Neurodegeneration](ideas/payload-oligodendrocyte-protection-therapy) | Novel target (oligodendrocyte) | 5 | 6 | 5 | 5 | 7 | 10 | 7 | 78 |
| 103 | [CD33 Modulation Therapy for Neurodegeneration](ideas/payload-cd33-modulation-therapy) | Novel target (TREM2-independent) | 9 | 6 | 5 | 5 | 4 | 4 | 8 | 74 |
| 104 | [Checkpoint Kinase Modulation Therapy for Neurodegeneration](ideas/payload-checkpoint-kinase-modulation-therapy) | Novel target (DNA damage checkpoint) | 8 | 8 | 6 | 5 | 5 | 0 | 8 | 72 |
| 105 | [Neuronal Calcium Sensor Modulation Therapy](ideas/payload-neuronal-calcium-sensor-modulation-therapy) | Novel target (calcium sensor) | 9 | 8 | 7 | 7 | 6 | 0 | 8 | 76 |
| 106 | [Cerebral Amyloid Angiopathy Therapy](ideas/payload-cerebral-amyloid-angiopathy-therapy) | Novel target (vascular Aβ) | 8 | 9 | 2 | 4 | 4 | 0 | 8 | 71 |
| 107 | [Vascular Dementia Combination Therapy](ideas/payload-vascular-dementia-combination-therapy) | Combination logic | 7 | 7 | 5 | 5 | 5 | 0 | 8 | 74 |
| 108 | [IRAK4 Kinase Modulation Therapy for Neurodegeneration](ideas/payload-irak4-kinase-modulation-therapy) | Novel target (TLR/IL-1R signaling) | 8 | 8 | 8 | 7 | 6 | 0 | 8 | 78 |
| 109 | [iPSC-Derived Glial Progenitor Cell Therapy for Neurodegeneration](ideas/payload-ipsc-glial-progenitor-cell-therapy) | Cell therapy (glial) | 8 | 8 | 9 | 6 | 7 | 8 | 7 | 74 |
| 110 | [P2X4/P2X7 Dual Receptor Modulation Therapy for Neurodegeneration](ideas/payload-p2x4-p2x7-dual-receptor-modulation-therapy) | Novel target (purinergic) | 9 | 9 | 9 | 7 | 6 | 5 | 8 | 75 |
| 111 | [AAV Serotype CNS Delivery Optimization Therapy](ideas/payload-aav-serotype-cns-delivery-optimization-therapy) | Delivery Innovation | 8 | 9 | 8 | 8 | 6 | 0 | 7 | 76 |
| 111 | [AAV Serotype CNS Delivery Optimization Therapy](ideas/payload-aav-serotype-cns-delivery-optimization-therapy) | Delivery Innovation | 8 | 9 | 7 | 7 | 6 | 5 | 7 | 77 |
| 112 | [Perivascular Space Drainage Enhancement Therapy](ideas/payload-perivascular-drainage-enhancement-therapy) | Novel target (glymphatic-lymphatic) | 9 | 8 | 9 | 8 | 5 | 0 | 8 | 85 |
| 118 | [Axonal Transport Rescue Therapy for Neurodegeneration](ideas/axonal-transport-rescue-therapy) | Novel target (kinesin-dynein) | 8 | 9 | 8 | 6 | 7 | 0 | 9 | 79 |

Placeholder Ideas (In Development)

The following ideas are placeholders in development. Once complete, they may be added to the ranked table:

• HIF-1α Stabilization Therapy — Novel target for hypoxia response (score: 69)

• FAK Inhibition Therapy — Targeting focal adhesion kinase (FAK) to modulate microglial phagocytosis, astrocyte reactivity, and synaptic remodeling (score: 74) — now available at [payload-fak-inhibition-neurodegeneration](ideas/payload-fak-inhibition-neurodegeneration)
• Pyroptosis Inhibition Therapy — Gasdermin inhibition for neuroprotection (score: 80) — now available at [content/ideas/payload-gasdermin-inhibition-therapy.md](payload-gasdermin-inhibition-therapy)

PSP-Specific Placeholder Ideas (In Development)

The following ideas are specifically relevant to Progressive Supranuclear Palsy (PSP), a 4R-tauopathy characterized by subcortical tau pathology, brainstem circuit dysfunction, and oculomotor impairment:

Completed from Placeholders (added to ranked table):

• 4R-Tau Targeting Therapy — Novel target for selective 4R-tau reduction (score: 79) — now available at [payload-4r-tau-targeting-therapy](ideas/payload-4r-tau-targeting-therapy)
• Brainstem Circuit Modulation Therapy — Novel target for brainstem circuit dysfunction (score: 75) — now available at [payload-brainstem-circuit-modulation-therapy](ideas/payload-brainstem-circuit-modulation-therapy)
• Tau Propagation Blocker Therapy — Payload design for 4R-tau propagation (score: 75) — now available at [payload-tau-propagation-blocker-therapy](ideas/payload-tau-propagation-blocker-therapy)

• PSP Combination Therapy — Combination logic for multi-target approach (score: 77) — now available at [payload-psp-combination-therapy](ideas/payload-psp-combination-therapy)

MSA-Specific Placeholder Ideas (In Development)

The following ideas are specifically relevant to Multiple System Atrophy (MSA), an α-synucleinopathy characterized by autonomic failure, cerebellar ataxia, and parkinsonism.

Completed from Placeholders (added to ranked table):

• Alpha-Synuclein Aggregation Inhibition Therapy — Novel target for α-syn oligomerization (score: 76) — now available at [payload-alpha-synuclein-aggregation-inhibition-therapy](ideas/payload-alpha-synuclein-aggregation-inhibition-therapy)
• MSA Combination Therapy — Combination logic for multi-target approach (score: 77) — now available at [payload-msa-combination-therapy](ideas/payload-msa-combination-therapy)
• Cerebellar Circuit Protection Therapy — Novel target for cerebellar ataxia (score: 74) — now available at [payload-cerebellar-circuit-protection-therapy](ideas/payload-cerebellar-circuit-protection-therapy)
• Autonomic Dysfunction Targeting Therapy — Novel target for autonomic failure (score: 72) — now available at [payload-autonomic-dysfunction-targeting-therapy](ideas/payload-autonomic-dysfunction-targeting-therapy)

Category Breakdown

Novel Targets

• CB1 Receptor Endocannabinoid Modulation Therapy — FAAH-sparing anandamide reuptake inhibition to restore neuroprotective endocannabinoid signaling without hepatotoxicity risks of FAAH inhibitors. Addresses excitotoxicity, neuroinflammation, mitochondrial dysfunction, and autophagy deficits across AD, PD, and ALS. CSF anandamide levels enable patient enrichment and pharmacodynamic monitoring.
• NRF2 Activator Therapy — targeting the NRF2-KEAP1 pathway to activate the antioxidant response element (ARE)-driven gene network. NRF2 controls over 500 protective genes including antioxidant enzymes (HMOX1, NQO1), detoxification enzymes, mitochondrial biogenesis factors, and anti-inflammatory mediators. Addresses the fundamental oxidative stress crisis in AD, PD, ALS, and aging. Strong synergy with NAD+/SIRT1 activators, mitophagy inducers, and anti-amyloid approaches.
• Axonal Transport Rescue Therapy — targeting the kinesin-dynein motor machinery to restore anterograde and retrograde axonal transport. Addresses tau-mediated, alpha-synuclein-mediated, TDP-43-mediated, and mutant huntingtin-mediated transport disruption across AD, PD, ALS, and HD. Five-pronged approach: kinesin activation, dynactin stabilization, microtubule acetylation (HDAC6), mitochondrial transport rescue (Miro1/TRAK), and AAV-KIF5A expression. Genetic validation from KIF5A, KIF1A, DCTN1 mutations in ALS/CMT/perry syndrome. Score 79/100.
• Neuronal Calcium Sensor Modulation Therapy — targeting the neuronal calcium sensor protein family (calbindin, parvalbumin, NCS1, VILIP) to restore calcium homeostasis disrupted in AD, PD, and ALS. Calbindin-expressing neurons are selectively spared in neurodegeneration. Strong synergy with calcium channel modulators and anti-excitotoxicity approaches.
• Microglia-state editing via TREM2, LXR signaling, and staged innate-immune recalibration.
• Astrocyte glutamate-buffer rescue via [EAAT2](genes/slc1a2), neuroinflammation, and excitotoxicity network suppression.
• VPS35 Retromer Stabilizer — retromer complex stabilization to restore lysosomal trafficking and reduce toxic protein accumulation.
• GPNMB Modulation — targeting lipid-laden microglia to restore phagocytic function and reduce neuroinflammation.
• SARM1 NADase Inhibitor for Axonal Preservation — targeting the TIR domain of SARM1 to block the catastrophic NAD+ depletion that drives axon fragmentation in ALS, PD, and peripheral neuropathies. One of the most genetically validated neuroprotective targets.
• TAM Receptor Modulation Therapy — targeting the TYRO3/AXL/MERTK receptor family to enhance microglial phagocytosis of apoptotic cells and protein aggregates (amyloid-beta, alpha-synuclein, TDP-43). Addresses impaired debris clearance across AD, PD, and ALS through multiple TAM receptor agonism.
• CX3CR1 Modulation Therapy — targeting the CX3CL1 (fractalkine)-CX3CR1 signaling axis to enhance neuron-microglia communication and suppress chronic neuroinflammation. CX3CR1 polymorphisms are linked to AD and PD risk. Highly synergistic with other microglia-targeting approaches (TREM2, TAM). Addresses neuroinflammation across AD, PD, and ALS through a distinct mechanism from TREM2/LXR.
• Focal Adhesion Kinase (FAK) Inhibition Therapy — targeting FAK to modulate microglial phagocytosis, astrocyte reactivity, and synaptic remodeling. FAK is a central signaling hub that coordinates cell adhesion, inflammation, and survival across glial and neuronal cell types. FAK inhibitors from oncology (defactinib, VS-4718) provide a strong foundation for CNS repurposing with established safety profiles. Highly synergistic with anti-aggregation and anti-inflammatory approaches.
• Oligodendrocyte Protection Therapy — Targeting PDGFRα, trophic factors (NRG1, IGF-1), and lactate transporters (MCT1) to preserve oligodendrocyte survival and myelin integrity. Addresses the fundamentally underappreciated white matter degeneration in MSA, PSP, PD, and AD. CSF MBP and ultra-high field MRI enable pharmacodynamic monitoring.
• TGF-β Modulation Therapy — targeting the transforming growth factor beta signaling pathway to restore neuroprotective signaling, reduce neuroinflammation, and promote tissue repair. Addresses impaired neuronal survival, glial dysfunction, and blood-brain barrier integrity across AD, PD, ALS, and FTD. Multiple intervention points (ligands, receptors, SMAD signaling) enable tailored approaches.
• USP13 Inhibitor — deubiquitinase inhibition to enhance mitophagy and synaptic proteostasis.
• Axonal Transport Rescue Therapy — targeting the kinesin-dynein motor machinery (KIF5A, KIF1A, dynein-dynactin complex) to restore bidirectional axonal transport disrupted by tau, alpha-synuclein, TDP-43, and mutant huntingtin. Five-pronged approach: kinesin activation, dynactin stabilization, HDAC6-mediated microtubule acetylation, Miro1/TRAK mitochondrial transport rescue, and AAV-KIF5A expression. Addresses a fundamental early event in neurodegeneration with strong genetic validation (KIF5A, DCTN1 mutations cause ALS and CMT2).
• cGAS-STING Pathway Inhibition — blocking the DNA-sensing innate immune axis that converts mitochondrial and nuclear DNA damage into chronic type I interferon-driven neuroinflammation. Directly addresses TBK1 loss-of-function mutations that cause familial ALS/FTD.
• IRAK4 Kinase Modulation Therapy — targeting the master upstream kinase in MyD88-dependent TLR/IL-1R signaling to control chronic neuroinflammation in AD, PD, and ALS. Unlike downstream NLRP3 inhibitors, IRAK4 modulation targets the initiating inflammatory cascade with broader coverage of TLRs 1-9. Strong synergy with TREM2, CD33, and anti-amyloid approaches.
• Ferroptosis Inhibition Therapy — targeting iron-dependent lipid peroxidation cell death through iron chelation, GPX4 activation, and lipid peroxidation inhibition. Addresses the fundamental vulnerability of neurons to ferroptotic cell death in AD, PD, and ALS.
• CRMP2 Phosphorylation State Modulation Therapy — targeting the cytoskeletal regulator CRMP2 (DPYS L2) through GSK-3β/CDK5 kinase inhibition and SUMOylation enhancement to restore axonal transport, synaptic vesicle trafficking, and mitochondrial distribution. Direct genetic link via CRMP2 mutations causing hereditary spastic paraplegia. Addresses axonal degeneration upstream of protein aggregation pathology across AD, ALS, and PD.
• ULK1/2 Kinase Modulation — small molecule ULK1/2 activators to enhance mitophagy clearance of damaged mitochondria. Addresses the AMPK-ULK1 axis that initiates autophagosome formation and directly phosphorylates PINK1 to enhance Parkin recruitment. Strong synergy with TFEB activators, VPS35 retromer stabilizers, and NAD+ boosters.
• Lipophagy Activation Therapy — targeting the lipid autophagy pathway to clear lipid droplet accumulation in neurons. Addresses lipotoxicity that contributes to neurodegeneration in AD, PD, and ALS. Complements general autophagy activation and metabolic modulators.
• LRRK2 Inhibitor Therapy — targeting the most common genetic cause of Parkinson's disease. LRRK2 G2019S and other mutations cause increased kinase activity leading to autophagy impairment, mitochondrial dysfunction, and dopaminergic neuron vulnerability. Small-molecule inhibitors reduce pathogenic kinase activity with biomarker validation (pLRRK2 S1292) for target engagement.
• Pyroptosis Inhibition Therapy — targeting gasdermin D (GSDMD)-mediated pyroptotic cell death to block the pro-inflammatory cell death pathway implicated in AD, PD, and ALS. Addresses both inflammatory cell loss and the release of inflammatory cytokines (IL-1β, IL-18) that drive chronic neuroinflammation. [@tan2014]
• SIRT2 Modulation Therapy — selective SIRT2 inhibition to reduce pathological tubulin deacetylation, modulate mitochondrial function, and attenuate neuroinflammation. Complements SIRT1 activation approach; addresses axonal transport deficits and metabolic dysfunction in AD, PD, and ALS.
• Gut-Microbiome-Targeted Therapeutic — targeting the microbiome-gut-brain axis through bacteriophage therapy, postbiotic metabolites (butyrate, urolithins), or engineered probiotics. Addresses peripheral inflammation that propagates to the CNS and leverages the emerging understanding of microbiome-brain connections in neurodegeneration.
• [Klotho Anti-Aging Therapy](ideas/payload-klotho-anti-aging-therapy) — anti-aging gene therapy and protein replacement targeting the Klotho (KL) aging-suppressor gene. Addresses fundamental age-related cognitive decline through multiple neuroprotective pathways including Nrf2-mediated oxidative stress reduction, NF-κB suppression, AMPK-driven autophagy enhancement, and synaptic plasticity preservation. Strong multi-disease potential for AD, PD, and ALS with active clinical trials.
• HSP90 Co-chaperone CDC37 Modulation — targeting the Hsp90-CDC37 co-chaperone complex to restore neuronal protein homeostasis. Unlike direct Hsp90 inhibitors (which cause broad toxicity), CDC37 modulation selectively reduces the folding burden of disease-associated misfolded proteins while preserves essential Hsp90 functions. Strong synergy with autophagy enhancers and relevance across AD, PD, ALS, and FTD.
• [RIPK1-TAK1 Interaction Inhibitor](ideas/payload-ripk1-tak1-inhibitor) — targeting the receptor-interacting protein kinase 1 (RIPK1) - transforming growth factor beta-activated kinase 1 (TAK1) protein-protein interaction to block necroptosis while preserving pro-survival NF-κB signaling. Unlike direct RIPK1 inhibitors (which can cause immunosuppression), this approach selectively disrupts the necroptotic signaling arm while maintaining NF-κB activation through TAK1. Addresses neuronal necroptosis in AD, PD, and ALS.
• TMEM175 Lysosomal K+ Channel Modulation — targeting the TMEM175 potassium channel, a major genetic risk factor for sporadic Parkinson's disease. TMEM175 regulates lysosomal acidification and autophagy function; PD risk variants compromise channel activity leading to impaired autophagic clearance of alpha-synuclein and mitochondrial dysfunction. First-in-class mechanism targeting a genetically validated PD risk locus with strong synergy potential with GBA modulators, TFEB activators, and LRRK2 inhibitors.
• WNT Signaling Modulation Therapy — targeting the dysregulated WNT pathway to restore neuroprotective signaling, enhance synaptic plasticity, and protect against amyloid and tau pathology. Addresses the fundamental decline in WNT-mediated neuroprotection that occurs with aging and neurodegeneration. Small molecule WNT agonists, GSK3B modulators, or AAV-mediated WNT ligand delivery can restore pathway homeostasis. Strong synergy with GLP-1 agonists, NRF2 activators, and anti-amyloid approaches.
• UFM1ylation Modulation for Proteostasis Restoration — targeting the UFM1 conjugation pathway to restore proteostasis, mitochondrial function, and ribosomal homeostasis. Addresses fundamental proteostasis network deficits in AD, PD, and ALS through a novel ubiquitin-like modification system. First-in-class mechanism with strong synergy with autophagy inducers and mitochondrial protectants.
• ATTEC Autophagy-Targeting Chimera — novel modality that engages the autophagy-lysosome pathway to degrade disease-causing proteins. Distinct from PROTACs, ATTECs can clear large protein aggregates (alpha-synuclein, tau, TDP-43) that exceed proteasome size limits. First-in-class for neurodegeneration with strong multi-disease potential (AD, PD, ALS, FTD).
• [Hippo Pathway Modulation Therapy for CBS](/ideas/payload-hippo-pathway-modulation-cbs) — Novel approach targeting YAP/TAZ nuclear translocation and MST1/2 inhibition to restore pro-survival signaling in CBS and related 4R tauopathies. Addresses the tau-induced YAP/TAZ sequestration and MST1/2 activation documented in CBS/PSP post-mortem brain tissue. First-in-class mechanism targeting neuronal survival pathways downstream of tau pathology. Strong synergy with tau-targeted therapies and neuroprotective approaches.
• UFM1ylation Modulation for Neurodegeneration — targeting the ubiquitin-like UFM1 conjugation system to restore ER stress response, mitochondrial protein quality control, and ribosome-associated quality control. UFM1ylation deficiency has been documented in AD/PD brain tissue, and enhancing this pathway addresses fundamental proteostasis failure across multiple neurodegenerative diseases.
• Cerebral Amyloid Angiopathy Therapy — targeting amyloid-beta deposition in cerebral blood vessels through apoE-dependent clearance, vascular smooth muscle cell protection, and LRP1-mediated perivascular drainage enhancement. Addresses the underappreciated vascular Aβ compartment distinct from brain parenchymal anti-amyloid approaches. Strong rationale for mixed AD/VaD and CAA-specific cognitive impairment.
• Neurovascular Coupling Restoration Therapy — targeting functional hyperemia impairment in neurodegenerative diseases via astrocyte calcium sensitization, pericyte relaxants, nitric oxide donors, and EET analogs to enhance neurovascular coupling responses.

Payload Design

• Conformer-selective tau-seed interception focused on extracellular propagation nodes in tauopathy and cbd-pathway.
• Tau-PROTAC heterobifunctional degrader — catalytic intracellular degradation of pathological tau via cereblon/VHL E3 ligase recruitment.
• mRNA-encoded intrabody for alpha-synuclein — LNP-mRNA delivering intracellular nanobodies that neutralize alpha-synuclein oligomers.
• CRISPRi epigenetic silencing of SNCA — dCas9-KRAB epigenetic repression of SNCA to reduce alpha-synuclein dosage below aggregation threshold.
• Molecular glue for TDP-43 clearance — small-molecule glue redirecting CRBN E3 ligase to degrade cytoplasmic TDP-43 aggregates.
• Synthetic gene circuit for GDNF — feedback-controlled GDNF expression circuit with dopamine-responsive promoter and doxycycline safety switch.
• Engineered iPSC-microglia cell therapy — CRISPR-engineered iPSC-derived microglia with enhanced TREM2 signaling for aggregate clearance.
• Adenine base editing of APOE4 — ABE conversion of APOE4 to APOE3 in astrocytes for Alzheimer's prevention.
• C9orf72 RNA-Targeting for DPR Reduction — ASO or RNAi-mediated reduction of mutant C9orf72 expression to decrease toxic dipeptide repeat proteins (poly-GA, poly-GP, poly-GR). Allele-specific targeting spares wild-type C9orf72 which is essential for lysosomal function.
• circRNA Dysfunction Restoration Therapy — Using ASO or CRISPR technology to restore dysfunctional circular RNA in neurons. Addresses the decline of neuroprotective circRNAs (like CDR1as/circRNA-7) that occurs in AD/PD, restoring miRNA sponge function and synaptic gene regulation.
• SARM1 NADase Inhibition for Axonal Preservation — Small-molecule inhibition of SARM1's NADase domain to prevent axonal degeneration. Addresses the obligate executioner of programmed axon death in ALS, PD, and peripheral neuropathies. One of the most genetically validated neuroprotective targets.
• AAV-Delivered RNA Targeting Therapy — AAV vectors carrying RNA-targeting payloads (ASO, RNAi, RNA aptamers) to reduce expression of toxic disease-driving proteins. Addresses monogenic forms of AD (APP, PSEN1), PD (SNCA, LRRK2), and ALS/FTD (C9orf72, SOD1). Single administration could provide years of benefit.

Delivery Innovation

• BBB-transcytosis shuttle for episodic CNS PROTAC delivery — Receptor-mediated transcytosis shuttles for intermittent CNS delivery of large targeted-degrader payloads.

Combination Logic

• SIRT1 Activation + NAD+ Precursor Combination Therapy — Synergistic epigenetic-metabolic rescue combining SIRT1 activators with NAD+ precursors (NR/NMN). Addresses the fundamental NAD+ depletion crisis in neurodegeneration while providing the deacetylase cofactor needed for SIRT1 activity. Three-phase protocol: NAD+ priming (weeks 1-4), combination therapy (weeks 5-16), maintenance. Strong rationale for AD, PD, ALS, and aging.
• CD38 Inhibition + NAD+ Precursor Synergy — Dual-target approach combining CD38 inhibitors with NAD+ precursors (NMN, NR) to achieve greater NAD+ repletion than either approach alone. CD38 inhibition prevents NAD+ breakdown while precursors boost biosynthesis. Addresses the fundamental NAD+ decline in aging and neurodegeneration through complementary mechanisms. Strong synergy with SIRT1 activators and autophagy enhancers.
• Intranasal Insulin + GLP-1 Combination Therapy — Synergistic metabolic rescue combining intranasal insulin delivery with GLP-1 receptor agonists. Addresses brain insulin resistance, a core pathology in AD and PD, through complementary PI3K/Akt pathway activation. Intranasal delivery bypasses BBB; GLP-1 agonists provide additional neuroprotection via reduced inflammation and enhanced mitochondrial function. Strong multi-disease potential for AD, PD, and aging.
• Mitophagy Gate Therapy: PINK1/Parkin + TFEB Priming — Dual-arm approach combining PINK1/Parkin-mediated mitophagy induction with TFEB lysosomal biogenesis priming. Addresses the full clearance pipeline rather than single bottlenecks. Staged dosing: TFEB priming (weeks 1-4), then PINK1/Parkin induction (weeks 5-12).
• [Astrocytic Mitochondrial Transfer + Metabolic Copacking](ideas/payload-astrocyte-mito-transfer-metabolic-copacking) — Combines astrocyte-mediated mitochondrial transfer enhancement (CX43 agonists, CD38 inhibitors, trafficking enhancers) with metabolic copacking (ketone esters, pyruvate dehydrogenase activators, creatine-citrate). Addresses the fundamental energy crisis in neurodegeneration by both increasing mitochondrial supply and improving substrate utilization. Strong rationale for AD, PD, and aging.
• Proteostasis Triad Pulses: ISR + Autophagy + Chaperone Induction — Pulsed, staggered intervention across all three pillars of the proteostasis network: integrated stress response modulation (ISRIB), autophagy induction (TFEB, rapamycin), and chaperone upregulation (HSP90 inhibitors). Addresses the fundamental bottleneck in neurodegeneration: simultaneous failure of multiple interconnected proteostasis mechanisms. Temporal staggering avoids adaptive downregulation.
• Autophagy-Proteostasis Dual Activation Therapy — Combines TFEB-mediated lysosomal autophagy activation with proteasome enhancement to achieve dual clearance of pathological proteins. Addresses both autophagy-lysosome and ubiquitin-proteasome system dysfunction that commonly co-occur in neurodegeneration. Staggered dosing prevents proteostasis exhaustion.
• Dual-node mitophagy plus lysosomal activation stacking (PINK1/Parkin, autophagy-lysosomal dysfunction).
• Vascular Dementia Combination Therapy — Multi-target approach combining vascular risk factor modulation, neuroprotection (cholinesterase inhibitors, memantine), and cerebral perfusion enhancement to address the three pillars of VaD: preventing progression, treating existing deficits, and restoring cognitive function.

Biomarker-Driven

• Longitudinal adjustment via GFAP, NfL, and fluid phospho-tau signatures.
• p-Tau217 Adaptive Dosing Protocol — Tau pathology burden tracking with dynamic dose titration based on p-tau217 trajectories.
• NfL-Guided Neuroprotection Threshold — Neurodegeneration gate using NfL as early warning signal to initiate preventive neuroprotection.
• sTREM2-Modulated Microglial Therapy — Microglial state modulation guided by sTREM2 as proxy for TREM2 activity.
• Neurogranin-Synapse Rescue Cascade — Synaptic integrity monitoring via neurogranin to guide rescue interventions.
• YKL-40 Anti-Inflammatory Cycling — Pulsed anti-inflammatory therapy synchronized to YKL-40 inflammatory peaks.
• Mitochondrial NAD Redox Swing Protocol — Temporal NAD+ precursor scheduling to amplify mitochondrial hormesis while avoiding adaptive downregulation. Morning high-dose NAD+ with exercise, evening dose reduction to allow natural redox cycling.

Repurposing and Regeneration

• NLRP3-coupled senomorphic cycles with already characterized small molecules and adaptive scheduling.
• Synapse-resilience circuit: BDNF plus sleep-glymphatic entrainment — Combined BDNF therapy with sleep architecture optimization to enhance synaptic resilience and glymphatic clearance. Addresses both structural integrity and nightly waste removal. Four-phase protocol: baseline assessment, sleep optimization, BDNF activation, and maintenance.

Prevention and Resilience

• [Prodromal Resilience Package for Genetically High-Risk Cohorts](ideas/payload-prodromal-resilience-package) — Precision prevention framework implementing biomarker-guided interventions for individuals with genetic risk factors (APOE4, LRRK2, GBA1, C9orf72, SOD1, GRN) before clinical symptoms appear. Addresses the prodromal window where pathology is present but neurons are still functional.
• [LRRK2 Kinase Modulation for Pre-symptomatic PD Prevention](ideas/payload-lrrk2-kinase-modulation-prevention) — Targets LRRK2 G2019S mutation carriers with pre-symptomatic kinase inhibition to prevent dopaminergic neuron loss. Leverages the 10-15 year prodromal window where biomarker changes are detectable but neurons remain functional.
• [GBA1 Enzyme Enhancement for Pre-symptomatic PD Prevention](ideas/payload-gba-enzyme-enhancement-prevention) — Uses pharmacological chaperones (ambroxol, LTI-291) to restore glucocerebrosidase activity in GBA1 mutation carriers. Addresses lysosomal dysfunction and alpha-synuclein accumulation before clinical PD develops.
• [Circadian Entrainment for Neurodegeneration Prevention](ideas/payload-circadian-entrainment-neuroprevention) — Implements light therapy, sleep scheduling, and behavioral entrainment to enhance glymphatic clearance, reduce neuroinflammation, and preserve neuronal function in at-risk individuals. A universal, non-pharmacological prevention approach.
• [Microbiome-Guided Prevention Bundle](ideas/payload-microbiome-guided-prevention-bundle) — Personalizes microbiome modulation through metagenomics profiling, targeted probiotics, prebiotics, and dietary interventions. Addresses gut-brain axis dysfunction that accelerates neurodegeneration in at-risk populations.
• [Senolytic Prevention Protocol](ideas/payload-senolytic-prevention-protocol) — Uses periodic dasatinib+quercetin or fisetin treatment to clear senescent cells that drive neuroinflammation through SASP secretion. Targets the fundamental aging mechanism underlying neurodegeneration risk.
• [Synaptic Resilience Enhancement](ideas/payload-synaptic-resilience-enhancement) — Multi-modal approach combining BDNF activation (exercise, 7,8-DHF), mitochondrial support (CoQ10), and calcium homeostasis modulation to preserve synaptic function in pre-symptomatic at-risk individuals. Directly targets the strongest correlate of cognitive decline.
• Klotho Therapy — anti-aging intervention targeting the Klotho aging-suppressor gene to preserve cognitive function and prevent neurodegeneration before symptom onset. Serum Klotho levels serve as biomarker for patient stratification and response monitoring.
• Pre-symptomatic protocols for APOE, LRRK2, GBA1, and C9orf72 risk populations.

Progressive Supranuclear Palsy (PSP) Mechanisms

Progressive Supranuclear Palsy is a 4R-tauopathy characterized by:

• Accumulation of 4-repeat tau in globus pallidus, subthalamic nucleus, and brainstem
• Oculomotor dysfunction (vertical gaze palsy)
• Axial rigidity and gait instability
• Subcortical cognitive decline

4R-Tau Targeting Mechanisms

• MAPT Exon 10 Splicing Modulation — ASO/RNAi approaches to shift splicing away from exon 10 inclusion, reducing 4R-tau production. MAPT H1 haplotype is the major genetic risk factor for PSP.
• 4R-Tau-Selective Aggregation Inhibitors — Small molecules that selectively bind and inhibit 4R-tau oligomerization without affecting 3R or 4R in healthy neurons.
• Tau Immunotherapy (4R-Selective) — Antibody approaches targeting 4R-tau conformers with enhanced specificity over 3R-tau.
• Tau PET for PSP — Develop and validate tau PET ligands (like [^11C]PBB3) for PSP-specific tau detection and treatment monitoring.

Brainstem Circuit Modulation

• Pedunculopontine Nucleus (PPN) Stimulation — Deep brain stimulation of PPN to address gait freezing and oculomotor dysfunction in PSP.
• GABAergic Circuit Enhancement — Modulation of GABAergic signaling in basal ganglia output nuclei (globus pallidus internus) to reduce excessive inhibition.
• Adaptive DBS Protocols — Closed-loop DBS systems that respond to real-time biomarker feedback for PSP-specific symptom control.
• Oculomotor Circuit Restoration — Targeting vertical gaze control pathways in the midbrain (riMLF, ZI) to preserve eye movements.

PSP-Specific Combination Approaches

• Tau Reduction + Neuroinflammation Modulation — Combining MAPT splicing modulators with NLRP3 or CD33 inhibition to address both tau pathology and microglial activation.
• Tau + Brainstem Circuit Support — Multi-modal therapy combining anti-tau approaches with PPN stimulation or GABAergic modulators.
• Biomarker-Guided Adaptive Therapy — Using p-tau181 and NfL as companion biomarkers to guide dosing and assess treatment response in PSP.

PSP-Relevant Novel Targets

• GSK-3β Modulation — GSK-3β hyperactivation promotes tau phosphorylation at multiple sites relevant to PSP pathology. Selective modulators could reduce pathogenic tau phosphorylation.
• Tyrosine Kinase Inhibitors — Src family kinases (Fyn, Lyn) are involved in tau phosphorylation and microglial activation in PSP. repurposing of tyrosine kinase inhibitors (e.g., bosutinib) may have utility.
• Progranulin Modulation — Progranulin haploinsufficiency is a risk factor for PSP-like pathology. Progranulin-enhancing therapies may benefit PSP.
• TREM2 Modulation in PSP — TREM2 variants are linked to PSP risk. Microglial state modulation via TREM2 agonists may reduce subcortical neuroinflammation.

Disease Coverage Matrix

| Idea | AD | PD | ALS | FTD | PSP | CBS | MSA | Aging |
|---|---|---|---|---|---|---|---|---|
| Microglia-state editing | Core amyloid/tau inflammation amplifier | Immune phenotype modulation in synucleinopathy | Secondary neuroinflammatory control | Strong in microglia-linked FTD variants | Subcortical neuroinflammation in brainstem nuclei | Cortical/subcortical inflammation in CBS | MSA placeholder | Inflammaging mitigation |
| Mitophagy gate therapy | Mitochondrial rescue in vulnerable cortical neurons | Core mechanism in Parkin/PINK1 PD | Motor neuron mitostasis support | Fits progranulin/lysosome biology | Mitochondrial dysfunction in subcortical structures | MSA placeholder | High relevance to age-related mitochondrial drift |
| Tau-seed interception | Directly addresses spread in AD tau stages | Limited direct use | Low | High value in PSP/CBD/FTD-tau | Core mechanism - 4R-tau propagation in subcortical networks | MSA placeholder | Moderate |
| EAAT2 reboot | Excitotoxicity damping in AD and vascular overlap | Network-stability support | Strong rationale in ALS glutamate stress | Moderate | Network stability in basal ganglia output | MSA placeholder | Moderate |
| NLRP3-coupled senomorphic cycling | Strong in AD microglial activation | Moderate in PD neuroinflammation | Emerging | Emerging | Brainstem microglial activation in PSP progression | MSA placeholder | Strong inflammaging fit |
| BBB shuttle PROTAC delivery | Enables CNS target-space expansion | Enables kinase/aggregation degraders | Potential for RNA-binding protein targets | Potential | 4R-tau degradation in subcortical targets | MSA placeholder | Platform-level |
| Synapse-resilience circuit | High synaptic failure relevance | Motor-cognitive network resilience | Limited/moderate | Moderate | Oculomotor and gait circuit resilience | MSA placeholder | High preventive potential |
| NAD redox swing protocol | Supports metabolic decline correction | Strong mitochondrial angle | Moderate | Moderate | Subcortical metabolic support | MSA placeholder | High |
| Proteostasis triad pulses | High for tau/amyloid proteostasis | High for alpha-syn handling | High for TDP-43/FUS stress | High for tau/TDP-43 | Core - 4R-tau proteostasis | MSA placeholder | Moderate |
| Prodromal resilience package | APOE-focused prevention | LRRK2/GBA1 prodromal windows | SOD1/C9orf72 surveillance use-case | MAPT/GRN/TMEM106B risk stratification | MAPT mutations and prodromal PSP surveillance | MSA placeholder | Very high |
| Tau-PROTAC degrader | Core tau pathology clearance | Limited | Low | High in FTD-tau/PSP/CBD | Core - 4R-tau degradation | MSA placeholder | Moderate |
| mRNA intrabody α-syn | Low | Core Lewy pathology clearance | Low | Low | Low | MSA placeholder | Low |
| CRISPRi SNCA silencing | Low | Core gene dosage reduction | Low | Low | Low | MSA placeholder | Moderate |
| Molecular glue TDP-43 | AD comorbidity (30-57%) | Low | Core ALS pathology (97%) | Core FTD-TDP (~50%) | Less relevant (4R-tau driven) | MSA placeholder | LATE (>20% aged) |
| Gene circuit GDNF | Low | Core DA neuron rescue | Low | Low | PPN circuit modulation for gaze dysfunction | MSA placeholder | DA decline mitigation |
| iPSC-microglia therapy | Core clearance restoration | Neuroinflammation control | C9orf72 microglial rescue | Microglial dysfunction | Subcortical microglial activation control | MSA placeholder | Inflammaging reversal |
| APOE4 base editing | Core genetic risk elimination | Low | Low | Low | Low | MSA placeholder | Cognitive preservation |
| p-Tau217 Adaptive Dosing | Core AD tau tracking | Limited | Limited | Emerging | Emerging (p-tau181 more relevant) | MSA placeholder | Limited |
| NfL-Guided Neuroprotection | Universal neurodegeneration gate | Strong | Strong | Strong | Strong (progression marker) | Strong | High |
| sTREM2 Microglial Modulation | AD microglia targeting | Strong | Emerging | Emerging | Emerging | MSA placeholder | Low |
| Neurogranin Synapse Rescue | Synaptic integrity restoration | Strong | Moderate | Moderate | Moderate (subcortical synaptic loss) | Moderate | Low |
| YKL-40 Anti-inflammatory Cycling | Chronic inflammation targeting | Strong | Strong | Moderate | Moderate | Moderate | Moderate |
| VPS35 retromer stabilizer | Lysosomal rescue in neurons | Strong in AD/PD | Strong in PD (PINK1/Parkin axis) | Moderate | Fits progranulin/lysosome | Moderate | Age-related trafficking decline |
| GPNMB modulation | Lipid-laden microglia rescue | Strong in AD (DAM) | Strong in PD/GBA-PD | Emerging | Emerging | Moderate | Inflammaging |
| USP13 inhibition | Mitophagy enhancement | Moderate | Strong (PINK1/Parkin) | Strong (TDP-43) | Moderate | Moderate | Mitochondrial aging |
| SARM1 NADase inhibition | Low-Medium (axonal transport deficits) | High (nigrostriatal axon preservation) | Core (motor axon degeneration) | Low | Moderate (brainstem axon involvement) | MSA placeholder | Axonal aging |
| cGAS-STING inhibition | Tau-induced nuclear envelope disruption; mtDNA leakage | mtDNA accumulation from mitophagy failure | TBK1 LOF mutations cause ALS/FTD; TDP-43 activates cGAS | Tau/TDP-43 converge on cytoplasmic DNA | Tau-driven cGAS activation in subcortical neurons | MSA placeholder | Age-related mtDNA accumulation |
| Klotho Therapy | Strong (cognitive preservation, amyloid reduction) | Strong (dopaminergic neuron protection) | Moderate (motor neuron protection) | Emerging | Emerging (brainstem protection) | MSA placeholder | Core anti-aging mechanism, cognitive preservation with age |
| C9orf72 RNA-targeting | Low (if TDP-43 pathology present) | Low | Core genetic cause (~40% familial ALS) | Core genetic cause (~25% FTD) | Low | MSA placeholder | Moderate (repeat instability with age) |
| UFM1ylation modulation | High (proteostasis restoration, Aβ/tau clearance) | High (mitochondrial function in PD) | Moderate (TDP-43 proteostasis) | Moderate | High (4R-tau proteostasis) | MSA placeholder | Core anti-aging mechanism, proteostasis decline with age |

PSP-Specific Therapy Coverage

| 4R-Tau Targeting Approaches | PSP Relevance | Score |
|---|---|---|
| MAPT exon 10 splicing modulators | Direct 4R-tau reduction | 78 |
| 4R-tau aggregation inhibitors | Block 4R-tau oligomerization | 75 |
| Tau PET ligands for PSP | Diagnostic and monitoring biomarkers | 72 |
| Anti-tau immunotherapy (4R-selective) | Antibody-mediated tau clearance | 74 |

| Brainstem Circuit Approaches | PSP Relevance | Score |
|---|---|---|
| Pedunculopontine nucleus stimulation | Gaze and gait dysfunction | 72 |
| GABAergic enhancement in basal ganglia | Reduce excessive inhibition | 70 |
| Deep brain stimulation optimization | Adaptive stimulation protocols | 73 |
| Oculomotor circuit restoration | Vertical gaze improvement | 71 |

| Combination Approaches | PSP Relevance | Score |
|---|---|---|
| Tau reduction + neuroinflammation | Multi-target synergy | 77 |
| Tau + brainstem circuit support | Address pathology + symptoms | 76 |
| Biomarker-guided adaptive therapy | p-tau181/NfL-guided dosing | 75 |

MSA-Specific Therapy Coverage

| Alpha-Synuclein Targeting Approaches | MSA Relevance | Score |
|---|---|---|
| Alpha-synuclein aggregation inhibitors | Core mechanism - block oligomerization | 76 |
| Anti-α-syn immunotherapy | Antibody-mediated clearance | 73 |
| SNCA gene silencing (CRISPRi/ASO) | Reduce production at source | 75 |
| Conformer-selective α-syn extracellular traps | Intercept spreading seeds | 74 |

| Autonomic Dysfunction Targeting | MSA Relevance | Score |
|---|---|---|
| Norepinephrine restoration therapy | Orthostatic hypotension management | 72 |
| Bladder dysfunction targeting | Urinary urgency/incontinence | 70 |
| Gastrointestinal motility agents | Dysphagia and GI dysmotility | 71 |
| Cardiovascular autonomic modulation | Baroreflex sensitivity enhancement | 73 |

| Cerebellar Circuit Protection | MSA Relevance | Score |
|---|---|---|
| Purkinje cell protection strategies | Cerebellar ataxia target | 74 |
| GABAergic enhancement in cerebellar nuclei | Reduce inhibitory-excitatory imbalance | 72 |
| Olivary nucleus targeting | Tremor and dysmetria control | 71 |
| Cerebellar oxidative stress mitigation | Mitochondrial protection in Purkinje cells | 73 |

| Combination Approaches | MSA Relevance | Score |
|---|---|---|
| α-syn reduction + autonomic support | Multi-target synergy | 77 |
| α-syn + cerebellar circuit protection | Address pathology + symptoms | 76 |
| Biomarker-guided adaptive therapy | NfL/α-syn oligomer-guided dosing | 75 |

CBS-Specific Therapy Coverage

| Hippo Pathway Approaches | CBS Relevance | Score |
|---|---|---|
| YAP/TAZ nuclear translocation activators | Core - restore pro-survival signaling | 76 |
| MST1/2 kinase inhibitors | Block apoptotic signaling | 74 |
| TEAD transcriptional agonists | Bypass YAP/TAZ defects | 72 |
| Tau-YAP dissociation agents | Block sequestration | 73 |

| Tau-Targeting + Hippo Combination | CBS Relevance | Score |
|---|---|---|
| Anti-tau + Hippo pathway modulation | Multi-target synergy | 78 |
| Tau immunotherapy + neuronal survival | Address pathology + symptoms | 77 |
| Biomarker-guided adaptive therapy | NfL/p-tau-guided dosing | 75 |

Category Interconnection Map

Top 10 Ideas

Idea 1: Microglia-state editing via TREM2-LXR pulse program

Why now: genetics and human biomarker work support microglial state transitions as causal amplifiers in AD and FTD.[@kerenshaul2017][@deczkowska2018] Instead of chronic immune suppression, this concept applies periodic agonist/antagonist cycling tuned to fluid biomarker trajectories.

Mechanistic stack: TREM2 signaling reinforcement, lipid-handling reset via LXR-linked networks, and anti-inflammatory phase locking with [NLRP3 inflammasome](mechanisms/nlrp3-inflammasome).[@heneka2013][@ising2019]

De-risking path: iPSC microglia co-culture with tau-seeded neurons, then humanized mouse validation with CSF GFAP and NfL as go/no-go readouts.

Idea 2: Mitophagy gate therapy: PINK1/Parkin plus lysosomal TFEB priming

Why now: mitochondrial dysfunction and lysosomal failure converge across AD, PD, and ALS.[@lin2006][@cermak2019]

Mechanistic stack: controlled mitophagy induction through PINK1/Parkin plus intermittent TFEB activation to avoid stalled autophagic flux.[@narendra2008][@settembre2011]

De-risking path: patient-derived neurons with mitochondrial stress signatures, then adaptive dose design using plasma metabolomic stress panels and digital motor endpoints.

Idea 3: Tau-seed interception using conformer-selective extracellular traps

Why now: extracellular tau seeds are increasingly measurable and linked to spread kinetics in primary tauopathies and AD.[@clavaguera2009][@mudher2017]

Mechanistic stack: engineered binders selective for pathogenic seed conformers deployed in intrathecal pulse dosing; co-use with intracellular anti-aggregation support.

De-risking path: seed-amplification assays, serial CSF phospho-tau species, and longitudinal PSP / CBD progression markers.

Idea 4: Astrocyte glutamate-buffer rescue with EAAT2 transcription reboot

Why now: excitotoxic stress remains a common terminal pathway, especially in ALS and mixed AD/vascular states.[@rothstein1995][@fontana2015]

Mechanistic stack: selective transcriptional upregulation of EAAT2/GLT-1 in astrocytes, paired with inflammatory-noise reduction and synaptic metabolic support.

De-risking path: human astrocyte-neuron systems measuring glutamate clearance kinetics, network hyperexcitability, and injury biomarkers.

Idea 5: NLRP3-coupled senomorphic cycling therapy

Why now: perpetual blockade risks immune fragility; senomorphic periodic schedules could reduce inflammatory burden while preserving host defense.[@flores2018][@yousefzadeh2018]

Mechanistic stack: staged suppression of [NLRP3 inflammasome](mechanisms/nlrp3-inflammasome) with recovery windows, synchronized to senescence-associated cytokine profiles. Novel senomorphic cycling paradigm uses biomarker-guided intermittent dosing rather than continuous blockade.

De-risking path: short-cycle biomarker trials in enriched inflammatory phenotypes with strict infection monitoring. Phase 1 biomarker profiling → Phase 2 dose-finding → Phase 3 efficacy signal.

Idea 6: BBB-transcytosis shuttle for episodic CNS PROTAC delivery

Why now: target classes implicated in neurodegeneration are often intracellular and historically undruggable with standard CNS pharmacology.[@niewoehner2014][@craig2023]

Mechanistic stack: receptor-mediated endothelial transport and controlled intracellular release of degraders targeting tau modifiers, alpha-syn processing factors, and kinase hubs.

De-risking path: non-human primate PK/PD with CSF target engagement assays and safety-focused cytokine panels.

Idea 7: Synapse-resilience circuit: BDNF plus sleep-glymphatic entrainment

Why now: synaptic failure and impaired glymphatic clearance jointly track cognitive decline in AD and prodromal neurodegeneration.[@selkoe2002][@xie2013]

Mechanistic stack: BDNF therapy and sleep architecture optimization to increase restorative oscillations and waste clearance.

De-risking path: EEG-derived slow-wave metrics, memory composites, and fluid markers integrated in adaptive treatment windows.

Idea 8: Mitochondrial NAD redox swing protocol with temporal dosing windows

Why now: chronic continuous NAD-precursor use may blunt adaptive stress biology; temporal scheduling may better restore homeostasis.[@covarrubias2021][@vannini2019]

Mechanistic stack: phased NAD precursors, exercise-synchronized oxidation windows, and intermittent mitochondrial hormesis.

De-risking path: repeated NAD metabolomics, mitochondrial respiration signatures, and orthostatic/sleep safety surveillance.

Idea 9: Proteostasis triad pulses: ISR modulation plus autophagy plus chaperone induction

Why now: single-pathway interventions often fail because aggregate-prone proteins exploit parallel proteostasis bottlenecks.[@hetz2017][@hipp2019]

Mechanistic stack: timed ISR dampening, autophagic throughput enhancement, and chaperone induction to move misfolded protein load across clearance checkpoints.

De-risking path: multiplex proteostasis biomarker panels and stage-specific dosing by disease phenotype.

Idea 10: Prodromal resilience package for genetically high-risk cohorts

Why now: biomarker-positive pre-symptomatic windows are now identifiable in several inherited risk groups.[@jack2018][@postuma2015]

Mechanistic stack: risk-genotype stratification, targeted lifestyle and pharmacologic micro-interventions, and dynamic biomarker gates before irreversible neuronal loss.

De-risking path: pragmatic platform trial design with adaptive enrollment, digital phenotyping, and pre-specified futility criteria.

Methodology

Scores were assigned by integrating: genetic support, disease-mechanism consistency, translational tractability, biomarker observability, and expected patient-level effect if the idea works as intended. Ranking favors ideas that are both mechanistically deep and testable in realistic near-term pipelines.

Validation History

• 2026-03-29 15:45 PT — Developed Complement Pathway Inhibition Therapy page (79/100). Created payload-complement-pathway-inhibition-therapy.md. Added to ranked table (rank 17, score 79). Multi-level strategy: C1q blockade (upstream), C3aR antagonism (midstream), C5 inhibition (downstream). Addresses pathological synaptic pruning, neuroinflammation, and myelin damage across AD, PD, ALS, HD. Reference validation passed (0 issues). Pipeline expanded to 130 therapeutic hypothesis pages.
• 2026-03-29 00:45 PT — Developed Vascular Dementia Combination Therapy page (74/100). Created payload-vascular-dementia-combination-therapy.md. Updated ranked table (now 107 ideas). Vascular contributions now fully covered in therapeutic pipeline. Reference validation passed.
• 2026-03-29 11:54 PT — Moved FAK Inhibition Therapy from placeholder to ranked table (74/100). Added to Category Breakdown. Reference validation passed.
• 2026-03-29 00:30 PT — Developed Cerebral Amyloid Angiopathy Therapy page (71/100). Created payload-cerebral-amyloid-angiopathy-therapy.md. Updated ranked table and Category Breakdown. Reference validation passed.
• 2026-03-23 15:35 PT — Developed MSA Combination Therapy page (77/100). Created payload-msa-combination-therapy.md. Updated ranked table (now 94 ideas). Reference validation passed.
• 2026-03-23 15:30 PT — Developed Cerebellar Circuit Protection Therapy page (74/100). Created payload-cerebellar-circuit-protection-therapy.md. Updated ranked table. Reference validation passed.
• 2026-03-23 15:25 PT — Developed Autonomic Dysfunction Targeting Therapy page (72/100). Created payload-autonomic-dysfunction-targeting-therapy.md. Updated ranked table. Reference validation passed.
• 2026-03-22 11:40 PT — Added MSA therapeutic ideas to Novel Therapy Index.
• 2026-03-22 11:30 PT — Added PSP therapeutic ideas to Novel Therapy Index. Added PSP column to disease coverage matrix (31 entries), created 4 PSP-specific placeholder entries (4R-tau targeting, brainstem circuit modulation, tau propagation blocker, PSP combination therapy), added PSP mechanisms to category breakdown, and updated action items. Reference validation passed.
• 2026-03-17 18:15 PT — Deepened NRF2 Activator Therapy page (82/100). Added new clinical trial references (NCT05198120 FIREFLY ALS, NCT04449666 AD) and updated references with recent NRF2 literature. Reference validation passed.
• 2026-03-17 13:39 PT — Developed CX3CR1 Modulation Therapy page (71/100). Added to ranked table (now 63 ideas). Fractalkine-CX3CR1 axis targeting microglia-neuron communication. Reference validation passed.
• 2026-03-17 13:00 PT — Developed CB1 Receptor Endocannabinoid Modulation Therapy page (79/100). Added to ranked table (now 62 ideas). FAAH-sparing anandamide reuptake inhibition mechanism. Reference validation passed.
• 2026-03-16 23:30 PT — Developed Adenosine A2A Receptor Antagonist Therapy page (75/100). Added to ranked table (now 61 ideas). Removed from placeholder section. Reference validation passed (90% inline coverage).
• 2026-03-16 15:24 PT — Developed TAM Receptor Modulation Therapy page (73/100). Added to ranked table (now 60 ideas). Removed from placeholder section. Reference validation passed.
• 2026-03-16 15:20 PT — Developed Sigma-1 Receptor Agonist Therapy page (76/100). Added to ranked table (now 59 ideas). Updated novel-therapy-index.
• 2026-03-16 09:14 PT — Verified pipeline: 62 idea files, 62 with references (100%), 55 with scores. All top 15 ideas have proper structure. Reference validation passed.

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• Progressive Supranuclear Palsy (PSP)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Coverage Gaps

Missing Disease Coverage

The current Novel Therapy Index covers Alzheimer's Disease, Parkinson's Disease, ALS, FTD, PSP, and Aging. The following neurodegenerative diseases are not yet represented in the disease coverage matrix:

• ~~Progressive Supranuclear Palsy (PSP)~~ — NOW COVERED (2026-03-22)
• ~~Corticobasal Syndrome (CBS)~~ — NOW COVERED (2026-03-28) — Hippo Pathway Modulation Therapy added
• ~~Multiple System Atrophy (MSA)~~ — NOW COVERED (2026-03-22)
• ~~Huntington's Disease~~ — NOW COVERED (2026-03-28) — HTT Gene Silencing Therapy added
• ~~Dementia with Lewy Bodies (DLB)~~ — NOW COVERED (2026-03-28) — Cholinergic Circuit Modulation Therapy added

Undeveloped Therapeutic Categories

The following therapeutic categories lack dedicated ranked pages:

• ~~Gene therapy delivery platforms~~ — NOW COVERED (2026-03-29) — AAV Capsid Engineering for CNS-Targeted Therapy added
• ~~RNA-targeting therapeutics — Antisense oligonucleotides for neurodegenerative diseases beyond C9orf72~~ — NOW COVERED (2026-03-29) — SOD1 Targeted RNA Silencing Therapy added
• ~~Cell therapy approaches~~ — NOW COVERED (2026-03-29) — iPSC-Derived Glial Progenitor Cell Therapy added

Underrepresented Mechanisms

The following mechanisms have placeholder mentions but lack full development:

• ~~Blood-brain barrier modulation~~ — NOW COVERED (2026-03-29) — Perivascular Macrophage Neuroprotection Therapy added
• ~~TREM2-independent microglial pathways~~ — NOW COVERED (2026-03-28) — CD33 Modulation Therapy added
• ~~Vascular contributions~~ — NOW COVERED (2026-03-29) — CAA Therapy and VaD Combination Therapy added
• ~~Metabolic therapies~~ — NOW COVERED (2026-03-28) — Ketone Body Therapeutic Strategy added
• ~~Oligodendrocyte targeting~~ — NOW COVERED (2026-03-28) — Oligodendrocyte Protection Therapy added

Action Items

References

Pathway Diagram

The following diagram shows the key molecular relationships involving Novel Therapy Index discovered through SciDEX knowledge graph analysis: