Profiling amyloid- peptides as biomarkers for cerebral amyloid angiopathy

Brain amyloid-beta (A beta) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the A beta(40) peptide, whereas A beta(42) is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other A beta isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various A beta isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of A beta(1-34), A beta(1-37), A beta(1-38), A beta(1-39), A beta(1-40), and A beta(1-42) were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six A beta peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for A beta(1-42) (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides A beta(1-42), none of the A beta peptides were decreased in AD-like subjects compared with controls. All A beta peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without A beta(1-42) in the model (since decreased A beta(1-42) served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF A beta profiles. Peptides shorter than A beta(1-42) were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal A beta accumulation. This study supports the potential use of this panel of CSF A beta peptides to indicate presence of CAA pathology with high accuracy.