This index provides a comprehensive overview of molecular and cellular targets being pursued for developing disease-modifying therapies for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), ALS, and related disorders. Each target is linked to detailed mechanism pages, treatment approaches, and the current drug development pipeline.
Neurodegenerative diseases share common pathological mechanisms including protein aggregation, mitochondrial dysfunction, neuroinflammation, and impaired autophagy. This page catalogs therapeutic targets across these mechanisms and their relationship to specific diseases.
The amyloid cascade hypothesis posits that accumulation of amyloid-beta (Aβ) plaques is the primary trigger in Alzheimer's disease pathogenesis. Multiple therapeutic approaches target amyloid production, aggregation, and clearance.
| Target |
Description |
Related Proteins |
Treatment Approaches |
Pipeline Status |
| Amyloid-beta (Aβ42/Aβ40) |
Core pathogenic peptide forming plaques |
APP, BACE1, PSEN1, PSEN2 |
Immunotherapy, aggregation inhibitors |
Approved (Lecanemab, Donanemab, Aducanumab) |
| Amyloid Precursor Protein (APP) |
Source of all amyloid-beta peptides |
Multiple proteases |
Secretase modulators, gene therapy |
Research |
| BACE1 (Beta-secretase) |
Protease that initiates Aβ production |
BACE1 |
Small molecule inhibitors |
Failed (Verubecestat) |
| Gamma-secretase |
Final protease in Aβ production |
PSEN1, PSEN2, APH1, PEN2 |
Modulators vs inhibitors |
Failed (Semagacestat) |
Tau pathology correlates strongly with cognitive decline in AD and is the primary hallmark in tauopathies like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Tau-targeting therapies aim to reduce phosphorylation, aggregation, and propagation.
| Target |
Description |
Treatment Approaches |
Development Stage |
| Tau protein (MAPT) |
Microtubule-associated protein that forms NFTs |
Immunotherapy, ASO |
Phase 2/3 |
| Tau phosphorylation |
Abnormal phosphorylation by kinases |
Kinase inhibitors (GSK-3β, CDK5) |
Research |
| Tau aggregation |
Oligomerization and fibril formation |
Aggregation inhibitors |
Phase 2/3 |
| Tau propagation |
Prion-like spread between neurons |
Immunotherapy |
Phase 2 |
Alpha-synuclein (α-Syn) aggregation is the central pathogenic mechanism in Parkinson's disease and related synucleinopathies. Multiple therapeutic strategies aim to reduce α-Syn production, aggregation, or enhance clearance.
| Target |
Description |
Treatment Approaches |
Development Stage |
| α-Synuclein (SNCA) |
Prion-like protein forming Lewy bodies |
Immunotherapy, ASO, small molecules |
Phase 2 |
| α-Synuclein aggregation |
Oligomer and fibril formation |
Aggregation inhibitors |
Phase 1/2 |
| α-Synuclein clearance |
Autophagy and lysosomal degradation |
Gene therapy, autophagy enhancers |
Research |
Chronic neuroinflammation driven by activated microglia is a common feature across neurodegenerative diseases. Targeting inflammatory pathways offers potential for disease modification.
| Target |
Description |
Treatment Approaches |
Development Stage |
| TREM2 |
Microglial receptor regulating phagocytosis |
Agonistic antibodies |
Phase 2/3 |
| NLRP3 Inflammasome |
Inflammatory cytokine activation |
Small molecule inhibitors |
Preclinical |
| CD33 |
Microglial receptor affecting Aβ clearance |
Antibody therapy |
Preclinical |
| CSF1R |
Microglial survival factor |
Kinase inhibitors |
Research |
| TYROBP (DAP12) |
TREM2 signaling adaptor |
Gene therapy |
Research |
Approximately 10-15% of PD cases are linked to monogenic causes. Several genetic targets are being pursued for disease-modifying therapies.
| Gene |
Protein |
Function |
Treatment Approach |
| LRRK2 |
Leucine-rich repeat kinase 2 |
Kinase regulating autophagy |
LRRK2 inhibitors |
| GBA |
Glucocerebrosidase |
Lysosomal enzyme |
GCase chaperones |
| SNCA |
Alpha-synuclein |
Protein aggregation |
ASO, gene therapy |
| PARKIN |
Parkin |
E3 ubiquitin ligase |
Gene therapy |
| PINK1 |
PTEN-induced kinase 1 |
Mitochondrial quality control |
Gene therapy |
| DJ1 |
DJ-1 |
Oxidative stress response |
Gene therapy |
Mitochondrial dysfunction is a hallmark of neurodegeneration, with impaired energy production, increased oxidative stress, and defective quality control.
| Target |
Description |
Treatment Approaches |
| Complex I |
Electron transport chain deficits |
Gene therapy, small molecules |
| TFAM |
Mitochondrial transcription factor |
Gene therapy |
| PGC-1α |
Mitochondrial biogenesis regulator |
PPAR agonists |
| Mitophagy regulators |
PINK1, PARKIN pathway |
Gene therapy, small molecules |
The proteostasis network declines with age, leading to accumulation of misfolded proteins. Enhancing protein clearance pathways is a promising therapeutic strategy.
| Target |
Pathway |
Treatment Approaches |
| Autophagy-lysosome pathway |
Protein clearance |
TFEB activators, autophagy enhancers |
| Ubiquitin-proteasome system |
Protein degradation |
Proteasome activators |
| Molecular chaperones |
Protein folding |
Chaperone inducers |
| mTOR |
Autophagy inhibition |
mTOR inhibitors |
While disease-modifying therapies are the ultimate goal, symptomatic treatments remain important for patient quality of life.
| Target Class |
Compounds in Development |
Key Targets |
| Anti-amyloid immunotherapy |
8+ |
Aβ, BACE |
| Anti-tau immunotherapy |
6+ |
Tau, phospho-tau |
| Neuroinflammation |
4+ |
TREM2, CD33 |
| Synaptic plasticity |
3+ |
Amyloid-binding |
| Target Class |
Compounds in Development |
Key Targets |
| Alpha-synuclein |
10+ |
SNCA, aggregation |
| LRRK2 |
4+ |
LRRK2 kinase |
| GBA/GCase |
3+ |
Glucocerebrosidase |
| Neuroinflammation |
5+ |
NLRP3, TREM2 |