Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease

Introduction Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers. Methods We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-beta (A beta)(x-38), A beta(x-40), A beta(x-42), as well as soluble amyloid precursor protein (sAPP)-alpha and sAPP-beta. Results sAPP-beta was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-beta moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses. Discussion SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-beta could be additional tools to diagnose SSVD. Highlights Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-beta and disturbances of the blood-brain barrier (BBB). This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD. Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.