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 (Aβ) and tau from the brain.
Cerebral amyloid angiopathy (CAA) — the accumulation of Aβ 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:
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 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 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 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 (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 |
The neurovascular space continues to attract interest:
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 |
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 |
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 |
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 |
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 |
| 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 |