This therapeutic concept proposes synaptic resilience enhancement for individuals identified as pre-symptomatic for neurodegenerative diseases. By targeting synaptic proteins (neurogranin), receptors, and downstream signaling pathways before significant synapse loss occurs, this approach aims to preserve cognitive function and prevent progression to clinical disease.
- Synapse loss correlates with cognitive decline: Post-mortem studies show synapse loss is the strongest correlate of cognitive impairment in both AD and PD
- Neurogranin is an early biomarker: Elevated CSF neurogranin predicts future cognitive decline in pre-symptomatic individuals
- Synaptic plasticity is modifiable: NMDA receptor modulation, BDNF signaling, and synaptic protein synthesis can be enhanced pharmacologically
- Early intervention critical: Synapse loss becomes irreversible once advanced; pre-symptomatic intervention offers the best chance of preservation
flowchart TD
subgraph Risk_Identification
A["Cognitive Testing<br/>RAVLT, ECAS"] --> B["CSF Neurogranin<br/>Elevated = synaptic vulnerability"]
B --> C["High Synaptic Risk"]
end
subgraph Intervention["Intervention"]
C --> D["NMDA Modulation<br/>Low-dose memantine"]
C --> E["BDNF Enhancement<br/>Exercise, pharmacologic"]
C --> F["Synaptic Protein Stabilization<br/>CK2 inhibition"]
end
subgraph Mechanisms["Mechanisms"]
D --> G["Enhance NMDA Signaling"]
E --> H["Boost Synaptic Plasticity"]
F --> I["Protect Synaptic Architecture"]
end
subgraph Outcome["Outcome"]
G --> J["Preserved Synaptic Density"]
H --> J
I --> J
J --> K["Maintained Cognitive Function"]
end
| Risk Category |
Profile |
Age Range |
Biomarker Criteria |
| High Risk |
Family history + elevated neurogranin |
50-70 |
CSF neurogranin > elevated |
| Moderate Risk |
Genetic risk (APOE4/LRRK2) |
45-65 |
Normal cognition, subtle deficits |
| Prodromal |
MCI with biomarker evidence |
55-75 |
MCI, positive AD/PD biomarkers |
- Low-dose memantine: Sub-antagonistic NMDA doses that enhance synaptic plasticity without causing adverse effects
- Lobeline: Amphetamine derivative that enhances dopamine release and protects synapses
- NSI-189: Novel compound that promotes hippocampal neurogenesis and synaptic protein expression
- Sage-217 (SAGE-217): GABA-A modulator in development for cognitive enhancement
- CK2 inhibition: Enhance synaptic protein synthesis and stability
- mGluR5 positive allosteric modulators: Enhance glutamate-dependent plasticity
- ** PDE5 inhibitors**: Enhance cGMP signaling to support synaptic plasticity
- Cognitive training: Structured cognitive exercises to maintain synaptic networks
- Aerobic exercise: Increases BDNF and promotes synaptic plasticity
- Sleep optimization: Sleep-dependent synaptic downscaling and memory consolidation
- CSF: Neurogranin, synaptic vesicle proteins (SV2C, synaptotagmin)
- Blood: BDNF, NFL for general neurodegeneration
- Imaging: Synaptic PET (SV2A ligands), FDG-PET for hypometabolism
- Cognitive: RAVLT, ECAS, MDS-UPDRS cognitive subscale
| Phase |
Design |
Population |
Primary Endpoint |
| II |
Randomized, placebo-controlled |
Elevated neurogranin, age 50-75 |
Change in synaptic PET at 12 months |
| III |
Factorial design |
Pre-symptomatic at-risk |
Time to cognitive impairment |