Bridging veins in Alzheimer's disease: Decoding waste clearance failure

Amid the rapidly increasing global burden of Alzheimer’s disease (AD) driven by population aging, amyloid-β (Aβ) deposition remains one of the earliest and defining pathological events, triggering a cascade of synaptic dysfunction, synapse loss, and cognitive decline. A particular detrimental manifestation of accumulation is cerebral amyloid angiopathy (CAA), in which Aβ deposits along cerebral vessel walls compromise vascular integrity and cerebral perfusion (Shin et al., 2007). Together, these observations underscore a central therapeutic goal: enhancing Aβ clearance to slow or prevent disease progression.

Because the brain lacks a conventional lymphatic network, cerebrospinal fluid (CSF) serves as its “lymph,” transporting metabolic waste from the central nervous system to maintain homeostasis. Clearance occurs through multiple routes, with the glymphatic system providing a dedicated brain-wide pathway. CSF enters periarterial channels from the subarachnoid space, where arterial pulsatility drives bulk flow (Iliff et al., 2012). Within the parenchyma, CSF exchanges with interstitial fluid (ISF) and exits along perivenous spaces. A defining feature of this system is its directional segregation: clean CSF flows into the brain along periarterial spaces, while waste-laden ISF exits along perivenous conduits and cranial or spinal nerves. A similar organization exists in the subarachnoid space, where leptomeningeal membranes partition pial periarterial and perivenous channels. Only at crossing points can tracers move from periarterial to perivenous compartments via pressure-driven exchange (Plog et al., 2025).

Bridging veins—extensions of pial veins that drain into the superior sagittal sinus (SSS)—traverse both the subarachnoid space and the arachnoid barrier. These vessels are best known as the principal source of subdural hemorrhage, particularly in aged individuals with increased vascular fragility (Mortazavi et al., 2013). The leptomeningeal layers ensheathe the bridging veins, forming fluid-filled perivenous tunnels that directly connect the pial perivenous spaces with the dura (Krisch et al., 1984) (see panels A and B of figure). At the interface where the veins penetrate the arachnoid barrier layer, they form arachnoid cuff exit (ACE) points (Smyth et al., 2024). At this junction, the perivenous spaces merge into the dural stroma, a layer containing fluid-filled compartments (Johnson, 2021) that interface with meningeal lymphatic vessels to channel waste-laden CSF out of the cranial cavity (Louveau et al., 2015). Bridging veins are located at the vertex, where they empty their contents into the SSS (see panel C of figure).

The perivascular spaces surrounding bridging veins are formed by the inner arachnoid layer, which extends upward along the veins and merges with the outer arachnoid layer at the ACE point (Krisch et al., 1984). This configuration establishes a secondary wall around the bridging veins, thereby creating a distinct perivenous compartment. How bridging veins remodel in pathological states such as AD—and how such remodeling of the surrounding perivenous impacts CNS waste clearance—remains poorly defined.

To answer this question, Smyth et al. (2025) investigated whether ACE points surrounding bridging veins are altered in AD using the 5XFAD mouse model. In 5XFAD dura, Aβ deposition was striking and largely confined to bridging veins, with Aβ detectable at ACE points even at early stages—supporting their role in waste clearance. Accumulation of Aβ at these sites reduced CSF efflux into the dura and impaired local vascular function. To assess cross-species relevance, postmortem dura from individuals with AD pathology and clinical dementia revealed a similar pattern: prominent Aβ deposition along bridging veins accompanied by degeneration of vascular smooth muscle cells. These findings suggest that dysfunction of ACE points at bridging veins may represent a previously unrecognized contributor to waste clearance impairment in AD.

Remarkably, amyloid at ACE points appeared early in the 5XFAD model, suggesting that bridging veins are particularly vulnerable and predispose to CAA. If these drainage structures are among the first to fail, impaired clearance at ACE points may not simply be a downstream consequence of plaque formation but rather an initiating event. This supports a feed-forward model in which early Aβ seeding at ACE points obstructs CSF efflux; reduced efflux slows removal of soluble Aβ and other metabolites; and impaired clearance increases local waste burden, accelerating further deposition. Such a self-reinforcing loop is pathologic—but also therapeutically promising—because ACE involvement emerges early. Preserving ACE patency or reducing perivenous amyloid might interrupt this cycle before widespread cortical pathology emerges. Moreover, if ACE-point obstruction indeed throttles CSF efflux, it may produce a detectable MRI signature that reflects this anatomical bottleneck. Identifying such a “CSF outflow blockade at venous exit sites” could yield a clinically useful, noninvasive biomarker for monitoring disease progression or therapeutic responses.

In 5XFAD mice, bridging veins exhibited reduced diameter and diminished blood flow, changes expected to alter intracranial pressure (ICP) and disrupt CSF circulation globally (Kamouh et al., 2025, Preprint). If bridging veins indeed participate in ICP regulation, the therapeutic significance of ACE points extends beyond AD to other CSF flow disorders, such as hydrocephalus and idiopathic intracranial hypertension, where CSF routing and pressure regulation are chronically impaired. This possibility suggests interventions aimed at maintaining or restoring ACE function could have broad translational relevance. However, defining precisely how ACE structures around bridging veins contribute to ICP control will require dedicated mechanistic studies.

The study by Smyth et al. raises several key challenges and questions regarding the role of ACE structures in waste clearance and AD. First, is bridging-vein amyloid the cause or the consequence of impaired clearance? During AD progression, does Aβ accumulate first at ACE points, physically constricting CSF outflow, or does CSF drainage slow for other reasons, such as aging, sleep disturbances, or meningeal lymphatic regression, thereby creating local stasis that promotes Aβ deposition? The distinction has direct therapeutic implications: if Aβ deposition initiates the process, strategies should focus on preventing or clearing Aβ at ACE points; if impaired drainage precedes deposition, preserving or restoring ACE-mediated outflow becomes the primary goal.

Second, because bridging veins connect the glymphatic and the meningeal lymphatic pathways, the dysfunction likely exerts system-level effects. Could enhancing bridging vein function improve overall CSF outflow, stabilize ICP, and thereby secondarily enhance glymphatic transport and meningeal lymphatic drainage—both of which are compromised in AD (Da Mesquita et al., 2021; Peng et al., 2016)?

Third, how can ACE function be safely restored? Bridging veins are mechanically delicate and susceptible to rupture, which can lead to subdural hemorrhage (Mortazavi et al., 2013). This vulnerability is exacerbated in aged individuals and in the presence of CAA. Thus, any attempt to therapeutically manipulate or “reopen” ACE structures must balance efficacy in restoring CSF efflux with the critical need to avoid venous injury and bleeding risk.

In conclusion, the bridging veins are not merely passive anatomical conduits but active participants in CSF outflow. The work by Smyth et al. on ACE points surrounding bridging veins in AD opens a new direction for the field, identifying CSF clearance at these sites as both a mechanistic insight and a potential therapeutic target for modifying disease progression.