This page ranks neurodegenerative disease mechanisms by their tractability for therapeutic intervention, considering factors including genetic validation, drug discovery history, and clinical feasibility. Targetability rankings help prioritize research investment and identify promising therapeutic approaches.
Targetability depends on multiple factors: druggability of the target, availability of relevant biomarkers, clinical trial design feasibility, and safety considerations.
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| Rank | Target | Mechanism | Drug Types Available | Clinical Stage |
|------|--------|-----------|---------------------|----------------|
| 1 | BACE1 | Amyloid production | Small molecule | Failed |
| 2 | AChE | Neurotransmission | Small molecule (approved) | Approved |
| 3 | NMDA receptor | Excitotoxicity | Small molecule (approved) | Approved |
| 4 | Amyloid-beta | Aggregation | Immunotherapy | Phase III |
| 5 | TREM2 | Microglia | Antibody | Phase II |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 6 |
Tau |
Aggregation |
Small molecule |
Phase II |
| 7 |
Tau |
Phosphorylation |
Kinase inhibitors |
Research |
| 8 |
Tau |
Immunotherapy |
Antibody |
Phase II |
| 9 |
HTR receptors |
Neurotransmission |
Small molecule |
Phase II |
| 10 |
PPAR |
Metabolism |
Small molecule |
Phase II |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 11 |
Autophagy |
Clearance |
Small molecule |
Preclinical |
| 12 |
NLRP3 |
Inflammation |
Small molecule |
Phase I |
| 13 |
APOE |
Clearance |
Gene therapy |
Preclinical |
| 14 |
Synaptic plasticity |
Function |
Various |
Research |
| 15 |
Neurogenesis |
Regeneration |
Various |
Research |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 1 |
DRD2 |
Dopamine receptor |
Agonist (approved) |
Approved |
| 2 |
MAO-B |
Dopamine metabolism |
Inhibitor (approved) |
Approved |
| 3 |
COMT |
Dopamine metabolism |
Inhibitor (approved) |
Approved |
| 4 |
ADORA2A |
Adenosine receptor |
Antagonist |
Phase III |
| 5 |
Alpha-synuclein |
Aggregation |
Immunotherapy |
Phase II |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 6 |
LRRK2 |
Kinase |
Small molecule |
Phase II |
| 7 |
GBA |
Enzyme |
Small molecule |
Phase II |
| 8 |
Glutamate receptors |
Excitotoxicity |
Modulators |
Phase II |
| 9 |
neurotrophic factors |
Neuroprotection |
Gene therapy |
Phase I/II |
| 10 |
Alpha-synuclein |
ASO |
Antisense |
Preclinical |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 11 |
PINK1/PARKIN |
Mitophagy |
Gene therapy |
Preclinical |
| 12 |
Alpha-synuclein |
Gene editing |
CRISPR |
Preclinical |
| 13 |
Glial modulation |
Support |
Various |
Research |
| 14 |
Iron chelation |
Oxidative stress |
Small molecule |
Phase II |
| 15 |
Circadian targets |
Rhythm |
Various |
Research |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 1 |
SOD1 |
Genetic |
ASO (approved) |
Approved |
| 2 |
Glutamate signaling |
Excitotoxicity |
Riluzole (approved) |
Approved |
| 3 |
C9orf72 |
Genetic |
ASO |
Phase I/II |
| 4 |
Neurotrophin support |
Protection |
Various |
Phase II |
| 5 |
Metabolic support |
Energy |
Various |
Phase II |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 6 |
FUS |
RNA processing |
ASO |
Preclinical |
| 7 |
TDP-43 |
Splicing |
ASO |
Preclinical |
| 8 |
ATXN2 |
RNA processing |
ASO |
Preclinical |
| 9 |
Inflammation |
Microglia |
Small molecule |
Phase II |
| 10 |
Cytoskeleton |
Transport |
Small molecule |
Research |
| Rank |
Target |
Mechanism |
Drug Types Available |
Clinical Stage |
| 11 |
Senolytics |
Cell death |
Various |
Preclinical |
| 12 |
RNA binding proteins |
Splicing |
Small molecule |
Research |
| 13 |
Epigenetic modifiers |
Transcription |
Various |
Research |
| 14 |
Muscle targets |
NMJ |
Various |
Research |
| 15 |
Regeneration |
Stem cells |
Cell therapy |
Research |
- GWAS hit strength
- Mendelian mutation validation
- Effect size and direction
- Biological plausibility
- Presence of druggable binding sites
- Protein family tractability
- Tissue delivery feasibility
- Biomarker availability
- Patient population size
- Trial endpoint validation
- Safety margin
- Market size
- Competition landscape
- Regulatory pathways
- Antisense oligonucleotides (ASOs)
- RNA interference (RNAi)
- Small interfering RNA (siRNA)
- AAV vectors
- CRISPR gene editing
- Base editing
- Stem cell replacement
- Gene-corrected cells
- Immunomodulation
The following therapeutic target areas need more detailed mechanism pages:
- Microglial modulation targets — TREM2 is covered but other microglia targets (CD33, PYROXIN, CCL2) are missing
- Autophagy enhancers — Listed as Tier 3 but needs dedicated page expansion
- Senolytics — Emerging area for ALS/PD, needs mechanism page
- Iron homeostasis — Listed for PD but mechanism page is thin
Targets that should link to detailed mechanism pages:
- LRRK2 — Should link to mechanisms/lrrk2-pathogenesis (currently missing)
- GBA/GCase — Should link to mechanisms/gba-lysosomal-function (needs creation)
- PINK1/PARKIN — Should link to mechanisms/mitophagy-pd (needs expansion)
- NLRP3 — Should link to mechanisms/nlrp3-neuroinflammation (needs creation)
- Create missing mechanism pages for Tier 2/3 targets to improve therapeutic pipeline visualization
- Add clinical trial status tables for each target category
- Cross-link drug candidates in development to mechanism pages