Profiling amyloid-ß peptides as biomarkers for cerebral amyloid angiopathy.

ABSTRACT

Brain amyloid-ß (Aß) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aß40 peptide, whereas Aß42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aß isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aß 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 Aß1-34, Aß1-37, Aß1-38, Aß1-39, Aß1-40, and Aß1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aß peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aß1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aß1-42, none of the Aß peptides were decreased in AD-like subjects compared with controls. All Aß 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 Aß1-42 in the model (since decreased Aß1-42 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 Aß profiles. Peptides shorter than Aß1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aß accumulation. This study supports the potential use of this panel of CSF Aß peptides to indicate presence of CAA pathology with high accuracy.