Amyloid () peptides are naturally occurring cleavage products of the amyloid precursor protein via sequential proteolytic processes called - and -secretase.1 A primary neuropathological hallmark of Alzheimer’s disease (AD) involves extracellular deposition to form senile plaques, leading to neuronal death and cognitive degeneration.2 Therefore, deposit elimination has been a major focus of -based AD therapeutics over the past decades. Currently, there are more than one hundred agents in clinical trials for AD therapeutics.3 Although, Aducanumab, an anti- human monoclonal antibody, was approved by the U.S. Food and Drug Administration in 2021 for early AD.4 The efficacy of this drug remains highly controversial.5,6 In addition, amyloid-related imaging abnormalities (ARIA) often co-occur during anti- immunotherapy (also seen with Aducanumab).7,8 The high incidence of ARIA makes it a major adverse effect of -targeted immunotherapies, which hinders the drug to reach the primary clinical endpoints.9 – 11 ARIA can be detected by magnetic resonance imaging (MRI) as hyperintensities on fluid-attenuated inversion recovery but is mostly asymptomatic.7,12 It is suggested that the phenomena might be due to the breakdown of the plaque, liberating abundant amount of soluble peptides that overwhelm the capacity of clearance through perivascular cerebrospinal fluid (CSF) bulk flow system.13 – 17 This leads to greater deposition in the vessel wall and causes a self-reinforcing cycle, thereby exacerbating the development of cerebral amyloid angiopathy (CAA), a common feature of AD that has been reported to affect 80% to 90% of AD cases.9,13,14,18,19 Besides, under pathological conditions of mild cognitive impairment and AD, the balance between production and clearance is disrupted so the decline of the clearance system, rather than the overproduction, contributes to deposition.20,21 Perivascular drainage is a major route of amyloid clearance from brain22 and a key contributor is the glymphatic system, which involves CSF entering the brain along paravascular spaces surrounding penetrating arteries and exchanging with interstitial fluid, which then exit the brain alongside veins.23 – 25 It has been reported that ventricular CSF clearance of is negatively related with the magnitude of brain deposition.26 Consequently, efficient clearance via the glymphatic transport system is crucial for maintaining brain health and efficacious AD therapeutics; therefore, it is necessary to monitor the clearance dysfunction. Although ARIA occurs during anti- treatment, it does not correlate with the speed of elimination and might not have adequate sensitivity.27 Pathological modification to the cerebral vascular architecture represents one of the earliest events in the AD pathological cascade and are evident earlier than the classical hallmark of the disease, deposition, and the onset of cognitive impairment.28 – 30 While the significance of vascular dysfunction is widely appreciated, its pathological changes caused by the clearance deficit through glymphatic transport are not clear. This raises the urgent need to characterize and quantitively evaluate vascular modifications after overload in CSF in preclinical settings. This may help us unravel the direct vascular consequences of clearance dysfunction and may also guide better treatment adjustments in patients receiving -targeted immunotherapy.