This page provides a comprehensive comparison of therapeutic targets across major neurodegenerative diseases: Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD). The matrix covers protein aggregation targets, genetic risk factors, and disease-modifying approaches with their clinical development status.
| Target |
Gene |
Disease |
Mechanism |
Drug Candidates |
Trial Phase |
Company |
| Amyloid-beta |
APP |
AD |
Aβ plaque clearance |
Lecanemab, Donanemab, Aducanumab |
FDA Approved / Phase 3 |
Biogen, Eli Lilly, Roche |
| Tau protein |
MAPT |
AD/PSP/CBS |
Tau tangle reduction |
Semorinemab, Bepranemab, Tilavonemab |
Phase 2/3 |
AbbVie, Roche, Alector |
| Alpha-synuclein |
SNCA |
PD/DLB |
α-Syn clearance |
Cinpanemab, Prasinezumab, UB-312 |
Phase 2 |
Biogen, Roche, Vaxxinity |
| TDP-43 |
TARDBP |
ALS/FTD |
TDP-43 aggregation inhibitors |
Preclinical compounds |
Preclinical |
Various |
| FUS protein |
FUS |
ALS |
Phase separation modulators |
Research stage |
Preacademic |
— |
| Target |
Gene |
Disease |
Risk Variant |
Therapeutic Approach |
Development Status |
| BACE1 |
BACE1 |
AD |
— |
BACE inhibitors |
Phase 2/3 (mixed results) |
| TREM2 |
TREM2 |
AD |
R47H (3x risk) |
TREM2 agonists |
Phase 2 (AL002 completed) |
| APOE |
APOE |
AD |
ε4 (3-4x risk) |
APOE modulators, gene therapy |
Preclinical/Phase 1 |
| LRRK2 |
LRRK2 |
PD |
G2019S (5-8x risk) |
LRRK2 inhibitors |
Phase 2/3 |
| GBA |
GBA |
PD |
L444P, etc. |
Gene replacement, small molecules |
Phase 1/2 |
| SNCA |
SNCA |
PD |
A53T |
ASO, RNAi, immunotherapies |
Phase 1/2 |
| SOD1 |
SOD1 |
ALS |
A4V, D90A, G93A |
ASO (Tofersen), gene therapy |
NDA Filed (Tofersen) |
| C9orf72 |
C9orf72 |
ALS/FTD |
Hexanucleotide repeat |
ASO, gene editing |
Phase 1/2 |
| FUS |
FUS |
ALS |
Missense mutations |
ASO, small molecules |
Preclinical |
| GRN |
GRN |
FTD/ALS |
Null mutations |
Gene therapy, protein therapy |
Phase 1/2 |
| Therapy |
Target |
Disease |
Mechanism |
Phase |
Key Trials |
| Lecanemab |
Aβ (protofibrils) |
AD |
Plaque clearance |
Approved |
CLARITY-AD |
| Donanemab |
Aβ (plaques) |
AD |
Plaque clearance |
Approved |
TRAILBLAZER-ALZ 2 |
| Cinpanemab |
α-Syn |
PD/DLB |
Lewy body clearance |
Phase 2 |
SPARKE |
| Prasinezumab |
α-Syn |
PD |
α-Syn reduction |
Phase 2 |
PASED |
| Semorinemab |
Tau |
AD |
Tau neutralization |
Phase 2 |
Laurion |
| AL002 |
TREM2 |
AD |
Microglial activation |
Phase 2 |
INVOKE-1 (did not meet primary) |
| ASO |
Target |
Disease |
Route |
Development Status |
| Tofersen |
SOD1 |
ALS |
Intrathecal |
NDA filed (2024) |
| WVE-004 |
SOD1 |
ALS |
Intrathecal |
Phase 1/2 |
| BIIB080 |
MAPT |
AD |
Intrathecal |
Phase 1 |
| ION363 |
FUS |
ALS |
Intrathecal |
Preclinical |
| ASO-C9orf72 |
C9orf72 |
ALS/FTD |
Intrathecal |
Phase 1/2 |
| Therapy |
Target |
Disease |
Delivery |
Status |
| AAV-GDNF |
GDNF |
PD |
Stereotactic |
Phase 1/2 |
| AAV-BDNF |
BDNF |
AD |
Stereotactic |
Phase 1/2 |
| PBFT02 |
GRN |
FTD |
Intracisterna magna |
Phase 1b |
| AVB-101 |
GRN |
FTD |
Intrathalamic |
Phase 1/2 |
| Zolgensma |
SMN1 |
SMA |
IV |
Approved |
| Compound |
Target |
Disease |
Mechanism |
Phase |
| GLP-1 agonists |
GLP-1R |
AD/PD |
Neuroprotection, anti-inflammatory |
Phase 2/3 |
| Rapamycin |
mTOR |
AD/PD |
Autophagy induction |
Phase 2 |
| Nilotinib |
BCR-ABL/c-Abl |
PD |
Autophagy, α-Syn clearance |
Phase 2 |
| Arimoclomol |
HSP90 |
ALS |
Protein folding |
Phase 3 |
| Target |
AD |
PD |
ALS |
FTD |
| Aβ (APP/BACE1) |
●●● |
— |
— |
— |
| Tau (MAPT/GSK3B) |
●●○ |
— |
— |
○ |
| α-Syn (SNCA/LRRK2) |
○ |
●●● |
— |
— |
| TREM2 |
●●○ |
— |
— |
— |
| APOE |
●●○ |
— |
— |
○ |
| SOD1 |
— |
— |
●●● |
— |
| C9orf72 |
— |
— |
●●○ |
●●○ |
| FUS |
— |
— |
●●○ |
○ |
| GRN |
○ |
— |
○ |
●●● |
Legend: ●●● = Primary disease target, ●●○ = Active development, ○ = Research/preclinical
| Category |
Phase 3 |
Phase 2 |
Phase 1 |
Approved |
| Anti-amyloid |
3 |
8 |
5 |
3 |
| Anti-tau |
2 |
12 |
6 |
— |
| Neuroprotection |
4 |
15 |
10 |
1 |
| Metabolic |
2 |
8 |
5 |
— |
| Category |
Phase 3 |
Phase 2 |
Phase 1 |
Approved |
| Disease modification |
2 |
8 |
4 |
— |
| Gene therapy |
1 |
3 |
2 |
— |
| Cell therapy |
— |
2 |
3 |
— |
| α-Syn targeting |
2 |
4 |
3 |
— |
| Category |
Phase 3 |
Phase 2 |
Phase 1 |
Approved |
| SOD1 targeting |
1 |
2 |
2 |
NDA filed |
| C9orf72 targeting |
— |
2 |
3 |
— |
| Neuroprotection |
3 |
5 |
4 |
2 |
| Gene therapy |
— |
2 |
4 |
— |
| Category |
Phase 3 |
Phase 2 |
Phase 1 |
Approved |
| GRN targeting |
— |
2 |
3 |
— |
| C9orf72 targeting |
— |
1 |
2 |
— |
| Tau targeting |
1 |
3 |
2 |
— |
| TDP-43 targeting |
— |
1 |
2 |
— |
| Mechanism |
AD |
PD |
ALS |
FTD |
| Neuroinflammation |
● |
● |
● |
● |
| Protein aggregation |
● |
● |
● |
● |
| Mitochondrial dysfunction |
● |
● |
● |
● |
| Autophagy impairment |
● |
● |
● |
● |
| Oxidative stress |
● |
● |
● |
● |
- GLP-1 Receptor Agonists: Active in AD and PD trials (semaglutide, liraglutide)
- TREM2 Modulators: Microglial targeting in AD, potential for FTD
- NLRP3 Inhibitors: Neuroinflammation across diseases
- Autophagy Enhancers: Protein clearance (rapamycin, urolithin A)
- mTOR Modulators: Shared pathway in AD, PD, ALS
¶ Challenges and Considerations
- Biomarker validation: Correlating biomarker changes with clinical outcomes
- Patient stratification: Genetic and biomarker-based selection
- Delivery to CNS: BBB penetration remains a key hurdle
- Timing of intervention: Early intervention likely more effective
- Combination approaches: Synergistic targeting of multiple pathways
- AD: Heterogeneous pathology (Aβ, tau, inflammation)
- PD: Alpha-synuclein spread and alpha-synucleinopathy subtypes
- ALS: Rapid progression, multiple genetic causes
- FTD: Phenotypic heterogeneity, overlapping pathology
- Cummings et al., Alzheimer's disease drug development pipeline (2024)
- Pagano et al., Parkinson's disease drug pipeline (2024)
- Miller et al., Tofersen in SOD1-ALS (2022)
- Mummery et al., AL002 in early AD Phase 2 (2026)
- Baker et al., Mutations in progranulin cause FTD (2006)
- Guerreiro et al., TREM2 variants in AD (2013)
- Rosen et al., SOD1 mutations in familial ALS (1993)