This therapeutic concept targets the neurovascular coupling (NVC) dysfunction that precedes and exacerbates cognitive decline in Alzheimer's disease and other neurodegenerative disorders. Neurovascular coupling refers to the precise coordination between neuronal activity and cerebral blood flow - when neurons fire, nearby blood vessels dilate to deliver increased oxygen and glucose. This coupling is impaired early in AD, contributing to neuronal dysfunction before amyloid or tau pathology becomes widespread[1][2].
The NVC pathway involves:
In AD and aging, this pathway fails at multiple points:
The therapy aims to restore NVC by:
| Dimension | Score | Rationale |
|---|---|---|
| Novelty | 8 | Addresses early NVC dysfunction before amyloid/tau pathology - novel intervention window |
| Mechanistic Rationale | 9 | Strong evidence NVC impairment precedes clinical symptoms; multiple therapeutic nodes available |
| Addresses Root Cause | 8 | Targets metabolic insufficiency driving neurodegeneration, not just proteinopathy |
| Delivery Feasibility | 7 | Small molecules and biologics can target astrocyte/pericyte pathways |
| Safety Plausibility | 7 | Enhancing physiological blood flow has safety precedent |
| Combinability | 9 | Compatible with anti-amyloid, metabolic, and vascular therapies |
| Biomarker Availability | 8 | fMRI, ASL, and CBF measurements can track NVC response |
| De-risking Path | 7 | Existing NO donors, calcium modulators in pipeline |
Total: 72/100
| Disease | Coverage | Rationale |
|---|---|---|
| Alzheimer's Disease | 10 | Primary target - NVC impairment documented early |
| Vascular Dementia | 9 | Core mechanism involves CBF dysregulation |
| Aging | 8 | NVC declines with normal aging |
| Parkinson's Disease | 6 | CBF autoregulation impaired in PD |
| FTD | 5 | Some NVC components affected |
| DLB | 5 | Vascular contributions to Lewy body pathology |
Takano T, Tian GF, Peng W, et al. Astrocyte-mediated control of cerebral blood flow. Nature Neuroscience. 2014. ↩︎
Oses M, Ledo S, Hilczer J, et al. Neurovascular coupling dysfunction in Alzheimer's disease. Nature Reviews Neurology. 2023. ↩︎