Amyloidosis of bridging veins is a pathologic feature of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance dysfunction in AD. In postmortem human samples, we also found striking amyloidosis of the bridging veins of individuals with AD. Moreover, in human AD specimens, there was prominent bridging vein structural degeneration, indicating advanced pathology and stronger deficits in humans. We propose that bridging vein amyloidosis is an underrecognized pathophysiological correlate of AD that may impair CSF efflux, intracranial pressure, vascular reactivity, and vascular integrity.