Overview
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Neurovascular dysfunction represents a critical yet often underappreciated component of Alzheimer's disease pathogenesis. The neurovascular unit — comprising endothelial cells, pericytes, smooth muscle cells, and astrocyte end-feet — sustains the blood-brain barrier (BBB), regulates cerebral blood flow (CBF), and maintains the glymphatic clearance system essential for removing amyloid-beta (Abeta) and tau from the brain.
...Overview
Mermaid diagram (expand to render)
Neurovascular dysfunction represents a critical yet often underappreciated component of Alzheimer's disease pathogenesis. The neurovascular unit — comprising endothelial cells, pericytes, smooth muscle cells, and astrocyte end-feet — sustains the blood-brain barrier (BBB), regulates cerebral blood flow (CBF), and maintains the glymphatic clearance system essential for removing amyloid-beta (Abeta) and tau from the brain.
Cerebral amyloid angiopathy (CAA) — the accumulation of Abeta in cerebral vessel walls — affects approximately 80-90% of AD patients and represents a major contributor to hemorrhagic strokes and cognitive decline in AD. This category page catalogs companies targeting:
- Cerebral amyloid angiopathy (CAA) therapies
- Pericyte and mural cell function
- White matter integrity and leukoaraiosis
- Glymphatic system enhancement
- Cerebral blood flow improvement
- Blood-brain barrier restoration
Key Companies
BioClin Therapeutics / Roche
BioClin (acquired by Roche) developed BAN2401 (lecanemab), an anti-Aβ antibody that targets both soluble Aβ protofibrils and amyloid plaques, with demonstrated activity against vascular amyloid in CAA:
| Attribute | Details |
|-----------|---------|
| Focus | Anti-Aβ monoclonal antibody for CAA |
| Lead Candidate | BAN2401 (lecanemab) |
| Indication | Alzheimer's disease, Cerebral Amyloid Angiopathy |
| Stage | Approved (AD), Phase 3 (CAA) |
| Mechanism | Anti-Aβ protofibril selective antibody |
Scientific Rationale: BAN2401 targets Aβ protofibrils — the soluble, toxic aggregate species believed to be the primary form deposited in cerebral vessel walls in CAA. By targeting these protofibrils, BAN2401 may reduce both parenchymal and vascular amyloid burden.
Cerenis Therapeutics
Cerenis Therapeutics was developing CER209 (TORX), an LXR (Liver X Receptor) agonist designed to promote cholesterol efflux and reduce vascular amyloid deposition:
| Attribute | Details |
|-----------|---------|
| Focus | LXR agonist for vascular amyloid clearance |
| Lead Candidate | CER209 (TORX) |
| Indication | Cerebral Amyloid Angiopathy |
| Stage | Discontinued (2020) |
| Mechanism | LXR-mediated cholesterol efflux |
Notes: Cerenis aimed to increase ApoE-mediated clearance of Aβ from cerebral vessels by activating LXRs, which promote expression of cholesterol transporters (ABCA1, ABCG1). The program was discontinued due to safety concerns.
Alnylam Pharmaceuticals
Alnylam is pioneering RNA interference (RNAi) therapeutics with a focus on brain delivery through transferrin receptor (TfR)-targeting:
| Attribute | Details |
|-----------|---------|
| Focus | siRNA delivery to brain via TfR |
| Platform | GALNAC-conjugated siRNA with TfR targeting |
| Indication | CNS diseases including AD |
| Stage | Preclinical |
Innovation: Alnylam's TfR-targeted approach enables siRNA delivery across the BBB. The company is applying this platform to reduce production of amyloid precursor protein (APP) in the brain as a potential disease-modifying approach.
Denali Therapeutics
Denali Therapeutics is developing a transport vehicle platform (TV) enabled by the LRP1 (Low-Density Lipoprotein Receptor-related Protein 1) for enhanced brain delivery:
| Attribute | Details |
|-----------|---------|
| Focus | LRP1-based brain delivery platform |
| Platform | Transport Vehicle (TV) technology |
| Mechanism | LRP1-mediated transcytosis across BBB |
| Stage | Clinical (multiple programs) |
Notes: Denali's TV-platform enables therapeutic antibodies and enzymes to enter the brain at levels 10-30x higher than conventional delivery. The company is applying this to multiple CNS targets including Aβ clearance.
Cyclocera developed AC-1204 (Ketasulin), a compound designed to improve cerebral glucose metabolism:
| Attribute | Details |
|-----------|---------|
| Focus | Cerebral glucose metabolism |
| Lead Candidate | AC-1204 (Ketasulin) |
| Indication | Alzheimer's disease |
| Stage | Phase 3 (discontinued 2019) |
| Mechanism | Ketogenic agent |
Rationale: Cerebral glucose hypometabolism is a hallmark of AD that precedes cognitive symptoms. By providing an alternative fuel source (beta-hydroxybutyrate), Ketasulin aimed to improve neuronal energy supply and cognitive function.
Cereve (Mitochondrial Protection)
Cereve (formerly Edison Therapeutics) focused on mitochondrial protection in neurodegenerative disease:
| Attribute | Details |
|-----------|---------|
| Focus | Mitochondrial dysfunction in neurovascular unit |
| Lead Candidate | CVT-31345 |
| Stage | Preclinical |
| Mechanism | Mitochondrial ATP-sensitive potassium channel activators |
Additional Companies in Development
The neurovascular space continues to attract interest:
- AstraZeneca: Anti-Aβ antibodies with CAA indication
- Janssen/Johnson & Johnson: Various neurovascular programs
- Prothena: Anti-Aβ antibodies targeting vascular amyloid
- AC Immune: Tau and Aβ antibodies with vascular mechanisms
- Voyager Therapeutics: AAV gene therapy for neurovascular targets
Therapeutic Targets
1. Cerebral Amyloid Angiopathy (CAA)
CAA represents a primary target for neurovascular AD therapies:
| Target | Approach | Companies |
|--------|----------|------------|
| Aβ40 | Anti-Aβ40 antibodies | BioClin/Roche, Prothena |
| Vascular amyloid | LXR agonists | Cerenis (discontinued) |
| Vessel wall integrity | Pericyte stabilization | Cereve |
| Aβ clearance | Glymphatic enhancement | Multiple programs |
2. Blood-Brain Barrier Restoration
The BBB deteriorates in AD, contributing to pathology:
| Target | Approach | Companies |
|--------|----------|------------|
| Endothelial function | Tight junction restoration | Research |
| Pericyte coverage | PDGF-BB agonists | preclinical |
| Transport function | LRP1 activators | Denali |
| BBB permeability | TfR-targeted delivery | Alnylam |
3. Cerebral Blood Flow (CBF)
Reduced CBF is an early marker of AD:
| Target | Approach | Companies |
|--------|----------|------------|
| Vasodilation | NO donors | Research |
| Metabolism | Ketogenic agents | Cyclocera |
| Microvascular density | VEGF modulators | Research |
| Impaired autoregulation | Calcium channel modulators | Multiple |
4. Glymphatic System
The glymphatic system clears Aβ and tau during sleep:
| Target | Approach | Companies |
|--------|----------|------------|
| AQP4 polarization | Astrocyte modulation | Preclinical |
| Sleep optimization | Arousal modulation | Multiple |
| Intranasal delivery | Direct delivery | Research |
5. White Matter/Leukoaraiosis
White matter hyperintensities correlate with cognitive decline:
| Target | Approach | Companies |
|--------|----------|------------|
| Oligodendrocyte function | Neurotrophic support | Research |
| Myelin repair | Remyelination agents | Research |
| Vascular supply | White matter perfusion | Research |
Clinical Trial Landscape
| Company | Drug | Phase | Indication | Status |
|---------|------|-------|------------|--------|
| Roche/BioClin | BAN2401 (lecanemab) | Phase 3 | CAA | Ongoing |
| Alnylam | siRNA programs | Preclinical | AD | Development |
| Denali | TV-platform | Multiple | AD | Clinical |
| Prothena | Antibodies | Phase 1/2 | AD | Clinical |
Scientific Rationale
Evidence for Neurovascular Contributions to AD
Vascular amyloid (CAA): Aβ40 deposits in leptomeningeal and cortical vessels in ~80% of AD cases
Reduced cerebral blood flow: CBF reductions precede cognitive symptoms by years
BBB breakdown: Increased BBB permeability correlates with disease severity
Pericyte loss: Pericyte degeneration observed in AD brains leads to capillary leakage
Glymphatic dysfunction: Impaired Aβ clearance contributes to accumulationTherapeutic Implications
- Dual targeting: Both parenchymal and vascular amyloid may be necessary for complete Aβ clearance
- Vascular health: Neurovascular unit integrity is essential for drug delivery to brain
- Combination approaches: Targeting neurovascular dysfunction alongside amyloid/tau may improve outcomes
Cross-Links
- [Alzheimer's Disease Pipeline](/companies/ad-pipeline)
- [Emerging Novel Mechanism AD Companies](/companies/emerging-novel-mechanism-ad-companies-2024-2025)
- [Cerebral Amyloid Angiopathy](/diseases/cerebral-amyloid-angiopathy)
- [Neurovascular Unit](/mechanisms/neurovascular-unit)
- [Blood-Brain Barrier](/mechanisms/blood-brain-barrier)
- [Glymphatic System](/mechanisms/glymphatic-clearance)
- [APOE4 and Vascular Risk](/genes/apoe)
References
[BAN2401 (Lecanemab) for Cerebral Amyloid Angiopathy](https://clinicaltrials.gov/ct2/show/NCT03841555)
[Cerenis Therapeutics](https://www.cerenis.com)
[Alnylam siRNA Brain Delivery Platform](https://www.alnylam.com)
[Denali Transport Vehicle Technology](https://www.denalitherapeutics.com)See Also
- [TDP-43 Protein](/wiki/proteins-tar-db-protein) — associated_with