Molecular Pathogenesis of Cerebral Amyloid Angiopathy in Alzheimer's Disease: The Role of the Central Fibrinolytic Cascade at the Neurovascular Unit.

Alzheimer's disease (AD) is increasingly recognized as a multifactorial neurodegenerative disorder involving complex neurovascular pathology. Departing from classic neurocentric paradigms, this review provides a conceptually novel perspective on how vascular inflammation and dysfunction actively drive AD progression through the lens of cerebral amyloid angiopathy (CAA) pathology. We evaluate the bidirectional cascade between amyloid-β pathology and the neurovascular unit, highlighted by cerebrovascular alterations and blood-brain barrier disruption. Crucial for cerebral homeostasis, the central nervous system's fibrinolytic pathway plays a dual role in this cascade, where the dysregulation of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and plasminogen accelerates CAA. We posit that suppressed fibrinolytic activity impedes amyloid-β clearance, while aberrant plasminogen-amyloid-β interactions paradoxically trigger localized inflammatory and thrombotic cascades that exacerbate vascular injury. By looking beyond traditional, neuron-centered models of Alzheimer's, fibrinolytic regulation and vascular repair offer a powerful new way to intervene. Bringing these discoveries to the clinic means finding a way to clear amyloid-β without tipping the scale toward bleeding risks. If we can map these complex vascular-fibrinolytic links, we can open the door to early intervention to design targeted therapies that prevent vascular damage and fundamentally change the trajectory of CAA and Alzheimer's disease.