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Brain amyloid‐β (Aβ) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aβ40 peptide, whereas Aβ42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aβ isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aβ 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 Aβ1‐34, Aβ1‐37, Aβ1‐38, Aβ1‐39, Aβ1‐40, and Aβ1‐42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aβ peptides were observed in CAA patients compared with controls (p = 0.0005–0.03). Except for Aβ1‐42 (p = 1.0), all peptides were decreased in CAA compared with AD‐like subjects (p = 0.007–0.03). Besides Aβ1‐42, none of the Aβ peptides were decreased in AD‐like subjects compared with controls. All Aβ 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 Aβ1‐42 in the model (since decreased Aβ1‐42 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 Aβ profiles. Peptides shorter than Aβ1‐42 were decreased in CAA patients, but not AD‐like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aβ accumulation. This study supports the potential use of this panel of CSF Aβ peptides to indicate presence of CAA pathology with high accuracy. [ABSTRACT FROM AUTHOR]

Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPα and sAPPβ ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism. Inter-laboratory variation, biomarker comparison (sAPPα vs. sAPPβ) and clinical performance was determined in three laboratories using 60 samples of patients with subjective memory complaints, Alzheimer's disease, or frontotemporal dementia. All performance parameters of the assays were similar between labs and within predefined acceptance criteria. The only exceptions were minor out-of-range results for recovery at low concentrations and, despite being within predefined acceptance criteria, non-comparability of the results for evaluation of the dilutional linearity and hook-effect. Based on the inter-laboratory correlation between Lab #1 and Lab #2, the IBL-international assays were more robust (sAPPα: r2 = 0.92, sAPPβ: r2 = 0.94) than the Meso Scale Diagnostics (MSD) assay (sAPPα: r2 = 0.70, sAPPβ: r2 = 0.80). Specificity of assays was confirmed using assay-specific peptide competitors. Clinical validation showed consistent results across the clinical groups in the different laboratories for all assays. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, the study shows that the newly developed standard operating procedures provide highly useful tools for the validation of new biomarker assays. A recommendation was made for renewed instructions to evaluate the dilutional linearity and hook-effect. [ABSTRACT FROM AUTHOR]