Profiling amyloid‐β peptides as diagnostic biomarkers for cerebral amyloid angiopathy

Abstract

AbstractBackgroundAmyloid‐β (Aβ) deposits are the main pathological hallmark of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD). Vascular deposits in CAA mainly consist of Aβ40, whereas Aβ42 is the predominant peptide in parenchymal plaques in AD. The diagnostic accuracy of other Aβ species in CAA remains understudied. We aimed to investigate the biomarker potential of various Aβ peptides for the differentiation of sporadic (sCAA) and hereditary Dutch‐type CAA (D‐CAA) from AD and controls.MethodCerebrospinal fluid (CSF) Aβ38, Aβ40, Aβ42, and Aβ43 levels were quantified by immunoassays in discovery (26 sCAA patients, 40 controls) and validation cohorts (40 sCAA patients, 40 AD patients, 37 controls), and D‐CAA patients (10 presymptomatic, 26 controls; 12 symptomatic, 28 controls). In a subset of samples (25 sCAA, 50 AD, 23 controls), we confirmed results using an extended panel of Aβ peptides (including Aβ34, Aβ37, and Aβ39, but not Aβ43) quantified by liquid chromatography mass spectrometry (LC‐MS). Area‐under‐the‐curve (AUC) was calculated using receiver operating characteristic curve to assess diagnostic accuracies.ResultWe found decreased levels of all Aβ peptides (quantified by immunoassays) in sCAA and D‐CAA compared with controls (Figures 1 and 2). All Aβ peptides, except Aβ43, were also decreased in sCAA compared with AD (Figure 1). LC‐MS verified the lower CSF levels of six Aβ peptides in sCAA compared with controls (Figure 3). All peptides, except Aβ42, were also decreased in sCAA compared with AD. Single peptide levels (using either method) differentiated sCAA from AD (immunoassays AUC 0.68‐0.88; LC‐MS AUC 0.51‐0.75) and controls (immunoassays AUC 0.61‐0.95; LC‐MS AUC 0.69‐0.85). Combinations of all Aβ peptides differentiated sCAA from AD patients (immunoassays AUC 0.93; LC‐MS AUC 0.84) and controls (immunoassays AUC 0.89‐0.98; LC‐MS AUC 0.91) with high accuracy.ConclusionCAA and AD each show a distinct disease‐specific profile of CSF Aβ peptides. All peptides shorter than Aβ42 were consistently decreased in sCAA, but not in AD, compared with controls. A panel of CSF Aβ peptides may diagnose CAA with high accuracy, and could have the potential to exclude patients with high load of CAA from anti‐Aβ therapies to avoid adverse events associated with CAA.